bluuebunny/crossref_metadata_2025 huggingface dataset:
iIMPACT: integrating image and molecular profiles for spatial transcriptomics analysis
Authors: Jiang Xi , Wang Shidan , Guo Lei , Zhu Bencong , Wen Zhuoyu , Jia Liwei , Xu Lin , Xiao Guanghua , Li Qiwei
Published: June 2024

Current clustering analysis of spatial transcriptomics data primarily relies on molecular information and fails to fully exploit the morphological features present in histology images, leading to compromised accuracy and interpretability. To overcome these limitations, we have developed a multi-stage statistical method called iIMPACT. It identifies and defines histology-based spatial domains based on AI-reconstructed histology images and spatial context of gene expression measurements, and detects domain-specific differentially expressed genes. Through multiple case studies, we demonstrate iIMPACT outperforms existing methods in accuracy and interpretability and provides insights into the cellular spatial organization and landscape of functional genes within spatial transcriptomics data.
Data analysis plan of the OECD PaRIS survey: leveraging a multi-level approach to analyse data collected from people living with chronic conditions and their primary care practices in 20 countries
Authors: Groenewegen Peter , Spreeuwenberg Peter , Timans Rob , Groene Oliver , Suñol Rosa , Valderas Jose Maria , Rijken Mieke
Published: June 2024

Objective

In view of the increasing number of people with (multiple) chronic conditions, the Organisation for Economic Co-operation and Development (OECD) initiated the International Survey of People Living with Chronic Conditions (PaRIS survey), which aims to provide insight in patient-reported outcomes and experiences of chronic care provided by primary care practices to support policy development. The objective of this research note is to describe the structure of the data, collected in the PaRIS survey and how the data will be analysed in a multilevel approach for cross-country comparison.

Analysis plan

The data structure of the PaRIS survey represents three levels: countries/health systems, primary care practices and patients. Multilevel analysis is used because of its accuracy in estimating country-level outcomes, its flexibility in modelling relationships, and its opportunities in connecting to relevant policy questions. Country-level outcomes will be estimated to facilitate cross-country comparison and (future) within-country comparison over time. Characteristics of patients that potentially explain variation in patient-reported outcomes and experiences can be linked to primary care practice and country/health system characteristics. This makes it possible to address policy-relevant questions relating, e.g., to the impact of chronic care management on patients with a specific chronic condition.
Microbial reduction of prebagged human plasma using 405 nm light and its effects on coagulation factors
Authors: Stewart Caitlin F. , McGoldrick Preston , Anderson John G. , MacGregor Scott J. , Atreya Chintamani D. , Maclean Michelle
Published: June 2024

Bacterial contamination is the most prevalent infectious complication of blood transfusion in the developed world. To mitigate this, several ultraviolet light-based pathogen reduction technologies (PRTs), some of which require photo-chemicals, have been developed to minimize infection transmission. Relative to UV light, visible 405-nm light is safer and has shown potential to be developed as a PRT for the in situ treatment of ex vivo human plasma and platelet concentrates, without the need for photo-chemicals. This study investigates the effect of 405-nm light on human plasma, with focus on the compatibility of antimicrobial light doses with essential plasma clotting factors. To determine an effective antimicrobial dose that is compatible with plasma, prebagged human plasma (up to 300 mL) was seeded with common microbial contaminants and treated with increasing doses of 405-nm light (16 mW cm−2; ≤ 403 J cm−2). Post-exposure plasma protein integrity was investigated using an AOPP assay, in vitro coagulation tests, and ELISA-based measurement of fibrinogen and Protein S. Microbial contamination in 300 mL prebagged human plasma was significantly reduced (P ≤ 0.05) after exposure to ≤ 288 J cm−2, with microbial loads reduced by > 96.2%. This dose did not significantly affect the plasma protein quality parameters tested (P > 0.05). Increased doses (≥ 345 J cm−2) resulted in a 4.3% increase in clot times with no statistically significant change in protein activity or levels. Overall, this study has demonstrated that the effective microbicidal 405 light dose shows little to no negative effect on plasma quality.
Investigating the price volatility spillover effects in the poultry industry inputs market and the egg market in Iran: using the multivariate DCC-GARCH model
Authors: Javadi Akram , Ghahremanzadeh Mohammad , Soumeh Elham Assadi
Published: June 2024

Background

This paper investigates the effects of price volatility spillover in the poultry industry’s input markets, including soybean meal, day-old chicks and corn, and the foreign exchange market as an independent market, on the wholesale egg market in Iran. The experimental investigation is based on dynamic conditional correlation (GARCH-DCC). It is one of the most powerful and accepted methods for studying market volatility, whose representation is based on conditional variance. On the other hand, eggs are one of the main food items in the food basket of Iranian households, playing an important role in ensuring part of the food security of the country. However, the price volatilities of its inputs, which make up more than 70% of egg production costs, cause the instability of its price and the confusion of the producers of this sector. This is although in the relevant literature, there is little research on the issue of volatility spillover effects on agricultural product markets, especially in the country.

Results

The findings show that any shock in the input market leads to volatility and instability in the market; on the other hand, these volatilities maintain their stability. In addition, there is a spillover of exchange market volatility into corn and soybean meal input markets.

Conclusions

In that context, this article emphasizes the knowledge of market relationships and their consequences, thereby suggesting appropriate policies to control and support the domestic poultry industry.
Analysis of the effect of CYP2C19 gene properties on the anti-platelet aggregation of clopidogrel after carotid artery stenting under network pharmacology
Authors: Li Pengfei , Cao Mengying , Liu Ling , Chen Long , Liang Shuang , Wang Youbin
Published: June 2024

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.
A case of pseudo-Kaposi sarcoma with chronic limb-threatening ischemia
Authors: Tamaru Yuya , Kikuchi Shinsuke , Uramoto Takayuki , Takahashi Kazuki , Kamada Keisuke , Yoshida Yuri , Uchida Daiki , Nishio Takuya , Yamao Takeshi , Ishitoya Shunta , Kishibe Mari , Inaba Masashi , Hayashi Toshihiko , Ishida-Yamamoto Akemi , Azuma Nobuyoshi
Published: June 2024

Background

Pseudo-Kaposi sarcoma (PKS) is a rare vascular proliferative disease, caused by arteriovenous malformation (AVM) and chronic venous insufficiency. The lesions are characterized by purple or reddish-brownish papules, plaques, and nodules. Although benign, it is clinically similar to Kaposi's sarcoma (KS), a malignant disease, and must be differentiated by histopathological examination. We report a rare case of PKS with chronic limb-threatening ischemia (CLTI).

Case presentation

An 83-year-old man with diabetes mellitus (DM) presented to a local dermatology department with a complaint of a right second toe ulcer and was, thereby, referred to our department due to arterial bleeding during skin biopsy to exclude malignant diseases. Although the pulsation of dorsalis pedis artery of the affected limb was palpable, the skin perfusion pressure was only 20 and 30 mmHg on the dorsum and planter surface, respectively, indicating severe ischemia of toe and forefoot. Ultrasonography and computed tomography revealed an AVM around the right second metatarsophalangeal joint and occlusion of the right dorsalis pedis artery in the middle, indicating CLTI in the background. Pathological findings of the skin biopsy found capillary blood vessel proliferation, hemosiderin deposition, and extravascular red blood cell leakage in the dermal layer, which could be found in KS. However, CD34 was normally stained in the vascular endothelium, and human herpesvirus-8 staining was negative, resulting in the pathological diagnosis of PKS, a proliferative vascular lesion associated with AVM. The ulcer was spontaneously epithelialized, but 2 years later the ulcer recurred and infection developed, necessitating treatment for abnormal blood flow. Transarterial embolization using N-butyl 2-cyanoacrylate for the AVM controlled abnormal perfusion once; however, the procedure exacerbated perfusion of the toe, resulting in foot ulcer progression. Forefoot amputation with surgical excision of AVM was performed, and thereby, wound healing was achieved.

Conclusion

This is a rare case of PKS with CLTI complicated with AVM. As there is currently no established consensus on the treatment of PKS, the approach to treatment strategy should be tailored to the specific condition of each patient.
Contribution of wastewater irrigated vegetables to the prevalence of soil-transmitted helminth infection among female farmers in Addis Ababa, Ethiopia
Authors: Gurmassa Bethlhem Kinfu , Gari Sirak Robele , Solomon Ephrem Tefera , Goodson Michaela L. , Walsh Claire L. , Dessie Bitew K. , Alemu Bezatu Mengistie
Published: June 2024

Background

Untreated or inadequately treated wastewater carrying human feces can host helminth eggs and larvae, contaminating the soil and plants that are irrigated with it. In Addis Ababa, farmers use untreated wastewater to grow vegetables; however, there are little data currently available published on vegetables' contribution to the prevalence of helminth among female farmers along the Akaki River, in Addis Ababa, Ethiopia.

Methods

A cross-sectional study was conducted in Addis Ababa City in February 2022. A stratified random sampling method was used to sample farming households. The sample size for each district was determined by a proportional allocation to the total number of households in the area. Two hundred and fifty-two composite vegetable samples and 101 farmers’ stool samples were collected and analyzed for helminth prevalence. Data on socio-demographics were collected by trained data collators using a structured questionnaire. Kato-Katz concentration was used to detect STH from a stool sample. Stata version 14.0 was used to process the data. Poisson regression was used to identify the association between STH prevalence in the vegetable and the farm's stool.

Results

Helminths were found in 67.5% of vegetables sampled and 20.8% of female farmers' stools. Ascaris lumbricoides eggs (vegetable 48.4% and stool 9.9%) were identified in all analyzed samples. Hookworm eggs (vegetable 13.1% and stool 8.9%) and Trichuris trichiura eggs (vegetable 5.9% and stool 2%) were also isolated. The total number of helminth eggs present in wastewater-irrigated vegetables and female farmers’ stool had a positive association (p < 0.05) with a regression coefficient of 1.92 (95% CI = 1.56–2.28).

Conclusions

The study found a significant prevalence of helminth infections, particularly Ascaris lumbricoides, in stool and vegetable samples irrigated with wastewater. A clear association was found between vegetable production and a higher prevalence of helminth infections among female farmers. Therefore, it is important to ensure that farmers are educated in the importance of food washing and sanitation/hygiene practices when using wastewater irrigation for vegetable crops.

Graphical Abstract
CX3CL1-CX3CR1 axis protects retinal ganglion cells by inhibiting microglia activation in a distal optic nerve trauma model
Authors: Yu Huan , Shen Bingqiao , Han Ruiqi , Zhang Yang , Xu Shushu , Zhang Yumeng , Guo Yanzhi , Huang Ping , Huang Shouyue , Zhong Yisheng
Published: June 2024

Background

The chemokine CX3CL1 has been reported to play an important role in optic nerve protection, but the underlying mechanism is still unclear. CX3CR1, the only receptor of CX3CL1, is specifically expressed on retinal microglia, whose activation plays a role in the pathological process of optic nerve injury. This study aimed to evaluate whether CX3CL1 exerts optic neuroprotection by affecting the activation of microglia by combining with CX3CR1.

Methods

A mouse model of distal optic nerve trauma (ONT) was used to evaluate the effects of the CX3CL1-CX3CR1 axis on the activation of microglia and survival or axonal regeneration of retinal ganglion cells (RGCs). The activation of microglia, loss of RGCs, and damage to visual function were detected weekly till 4 weeks after modeling. CX3CL1 was injected intravitreally immediately or delayed after injury and the status of microglia and RGCs were examined.

Results

Increases in microglia activation and optic nerve damage were accompanied by a reduced production of the CX3CL1-CX3CR1 axis after the distal ONT modeling. Both immediate and delayed intravitreal injection of CX3CL1 inhibited microglia activation, promoted survival of RGCs, and improved axonal regenerative capacity. Injection with CX3CL1 was no longer effective after 48 h post ONT. The CX3CL1-CX3CR1 axis promotes survival and axonal regeneration, as indicated by GAP43 protein and gene expression, of RGCs by inhibiting the microglial activation after ONT.

Conclusions

The CX3CL1-CX3CR1 axis could promote survival and axonal regeneration of RGCs by inhibiting the microglial activation after optic nerve injury. The CX3CL1-CX3CR1 axis may become a potential target for the treatment of optic nerve injury. Forty-eight hours is the longest time window for effective treatment after injury. The study is expected to provide new ideas for the development of targeted drugs for the repair of optic nerve.
Non-cancer febrile neutropenia in children: pathogens, antimicrobial susceptibilities, and outcomes
Authors: Radwan Radwa Abdel-Raheem , Youssry Ilham , Afifi Rasha Abdelraouf Abdelzaiz , Banna Afaf Mohamed Samy El , Balah Mariam Mahmoud Mohammed , Mohammed Eman Abdel El Raouf
Published: June 2024

Background

Febrile neutropenia is a medical emergency and remains a significant cause of morbidity and mortality, it is defined as a temperature > 38.3 °C (101 °F), or a sustained temperature > 38.0 °C (100.4 °F) for more than 1 h in a neutropenic patient. Neutropenia is defined as a decrease in the absolute number of neutrophils in the blood < 1500 cells/ mm3 in children.

Aim of the study

To identify the specific pathogens causing infections, determine antimicrobial susceptibility, and identify factors associated with morbidity and mortality in febrile neutropenic children.

Methods

A prospective cohort study, 38 non-cancerous pediatric patients admitted with 61 febrile episodes, was conducted. Sepsis screen, pan-cultures, and tests to identify the causative pathogens and antimicrobial sensitivity were collected.

Results

Coagulase-negative staphylococci (CONS) infection accounted for 38.4% of all positive cultures, while Klebsiella infection represented 23%. SARS-CoV2 (severe acute respiratory syndrome coronavirus 2) virus infection accounted for 23% of febrile episodes that lead to COVID-19 (coronavirus disease of 2019) sickness; however, it did not significantly impact patients’ outcomes. Unfavorable outcomes were associated with higher C-reactive protein (CRP) levels, positive blood cultures, and gram-negative organisms (p =  < 0.001, 0.013, 0.038 respectively). Prolonged duration of fever and elevated CRP levels were significant predictors of poor outcomes in febrile neutropenia, with a sensitivity of 88.9% and 100% and specificity of 70.6% and 62.3%, respectively.

Conclusion

Among febrile neutropenic patients, CONS is the most common pathogen, while Klebsiella is the most common gram-negative infection. Gram-positive organisms predominate in bloodstream infections. Prolonged duration of fever and elevated CRP levels can significantly predict poor outcomes.
A survey on the management practices of graves’ disease by Egyptian physicians and a comparison to similar reports from USA, Italy, China, and Brazil
Authors: Elsherbiny Tamer Mohamed , El-Aghoury Aliaa Aly
Published: June 2024

Background

Graves’ disease is the commonest cause of hyperthyroidism in iodine replete areas. Following universal salt iodization, most Egyptians are considered iodine sufficient. The present study aims to report a survey of real-life practices in the management of graves’ disease among Egyptian physicians and compare them to other similar reports.

Methods

An online survey was sent to members and affiliates of Alexandria thyroid association. Egyptian physicians were surveyed about initial diagnostics workup, management of an index case of uncomplicated graves’ disease not desiring pregnancy. Two modified scenarios were proposed to the index case to survey the impact on treatment preferences. Anonymous responses were collected, analyzed, presented, and compared to other published similar reports.

Results

Sixty-eight participated out of 120 invited physicians (56.67%). Initial workup included TSH receptor antibodies 46/68 (67. 6%), thyroid ultrasound 45/68 (66.2%), and thyroid scintigraphy 25/68 (36.8%). Treatment preferences in the index case were antithyroid drugs (ATD’s) 52/68 (76.5%), radioiodine 12/68 (17.5%), and surgery 4/68 (6%). Compared to other reports, treatment preferences were almost identical to Italian ones, ATD’s (77.1%), radioiodine (16.2%), and surgery (4.5%). If the patient is complicated with graves’ orbitopathy, treatment preferences would change into ATD’s 37/67 (55%), radioiodine 1/67 (2%), radioiodine with corticosteroids 14/67 (21%), and surgery 15/67 (22%). If the patient is desiring pregnancy, treatment preferences would be ATD’s 32/68 (47%), radioiodine 5/68 (7.4%), and surgery 31/68 (45.6%).

Conclusion

A high participation rate was observed. Similar to other reports, medical treatment is the preferred modality of treatment in graves’ disease and surgery is the least utilized modality. Similar treatment preferences to Italians were observed in the index case.
Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Gupta Shilpa , Loriot Yohan , Van Der Heijden Michiel Simon , Bedke Jens , Valderrama Begoña Pérez , Kikuchi Eiji , Flechon Aude , Petrylak Daniel P. , De Santis Maria , Galsky Matt D. , Lee Jae-Lyun , Swami Umang , Sridhar Srikala S. , De Giorgi Ugo , Wright Phoebe , Lu Yi-Tsung , Guan Xuesong , Dillon Ryan , Homet Moreno Blanca , Powles Thomas
Published: June 2024

4502

Background: EV+P nearly doubled median progression-free survival and overall survival vs PBC in patients (pts) with previously untreated la/mUC in the phase 3 EV-302 trial. PROs are reported here. Methods: In EV-302 (NCT04223856) pts were randomized 1:1 to EV+P or PBC (gemcitabine with cisplatin or carboplatin). PRO assessments included the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), and the Brief Pain Inventory Short Form (BPI-SF) completed at baseline, weekly for 12 weeks (wks), then every 3 wks through survival follow-up, inclusive of the time post-progression. Time to pain progression (TTPP) and mean change from baseline in worst pain at wk 26 using the BPI-SF were prespecified analyses statistically tested using a gatekeeping strategy. Mean change from baseline through wk 26 and time to confirmed deterioration (TTCD) of EORTC-QLQ-C30 and BPI-SF domains were prespecified descriptive analyses. TTPP and TTCD were assessed using Kaplan-Meier methods. Results: Of 886 pts randomized, 731 (376 received EV+P; 355 PBC) completed baseline PRO questionnaires. Compliance rates differed between arms and remained >70% through wk 29 for EV+P and through only wk 17 for PBC. Median TTPP was 14.2 months (mos) with EV+P and 10.0 mos with PBC (hazard ratio [HR]=0.92; 95% CI=0.72, 1.17; 2-sided p-value=0.48). The least squares (LS) mean reduction in worst pain at wk 26 was numerically greater with EV+P vs PBC (-0.61 vs -0.03, LS mean difference [95% CI]: -0.58 [-1.05, -0.11] [nominal 2-sided p-value=0.015]). Pts with moderate to severe pain at baseline who were treated with EV+P (n=128, 34%) had a meaningful (>2 pt) improvement from baseline in BPI worst pain from wk 3 through 26. In EORTC QLQ-C30 Global Health Status/Quality of Life [GHS/QoL], EV+P demonstrated a transient worsening at wk 3 (-6.3) that returned to baseline from wks 4 through 26, while patients treated with PBC demonstrated deterioration from wk 1 through wk 17 (range -1.2 to -7.1) when scores returned to baseline. TTCD for EORTC QLQ-C30 GHS/QoL was 5.9 mos with EV+P vs 3.2 mos with PBC (HR = 0.98 [95% CI]: 0.79 – 1.2). Conclusions: Pts treated with EV+P have improved survival compared with PBC without detriment to quality of life and functioning, further supporting the value of EV+P for pts with la/mUC. Compliance, especially after progression, was lower than expected (particularly in the PBC arm) and may have impacted the results. Clinical trial information: NCT04223856 .
Camrelizumab plus apatinib for previously treated advanced adrenocortical carcinoma: A single-arm, open-label, phase 2 trial.
Authors: Wei Zhigong , Zhu Yuchun , Cai Lei , Peng Xingchen
Published: June 2024

4511

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with dismal prognosis. Therapeutic options for patients with advanced ACC after failure of standard treatments are limited. The clinical benefit of single-agent immunotherapy as second-line therapy was still unsatisfactory. Methods: This was an investigator-initiated, prospective, single-arm, open-label, phase 2 trial and conducted at a single medical center. Patients were eligible for inclusion if they were aged at least 18 years; were pathologically diagnosed as unresectable or metastatic ACC; had failed first-line therapy; had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; had at least one measurable lesion; and had adequate organ function. The key exclusion criteria included a history of treatment with immunotherapy, anti-angiogenic small molecule TKIs, or anti-angiogenic monoclonal antibodies; a history of uncontrolled hypertension; and a history of an autoimmune condition requiring systemic therapy. All study participants received camrelizumab 200 mg intravenously on the first day of each 3 week cycle, combined with apatinib 250 mg orally once per day until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR), defined as the proportion of participants with complete response (CR) or partial response (PR) per RECIST (version 1.1). Results: A total of 21 patients with advanced ACC received at least one dose of camrelizumab and apatinib. ORR was 52% (95% CI, 30 to 74), and the disease control rate was 95% (95% CI, 84 to 100), superior to PD-1 inhibitor monotherapy and first-line standard therapy. The median PFS was 12.6 months (95% CI, 8.4 to 20.9), and the median OS was 20.9 months (95% CI, 11.0 to 20.9). The most common grade 3—4 treatment-related adverse events were alanine aminotransferase elevation (28.6%), aspartate aminotransferase elevation (23.8%) and lymphopenia (23.8%). Our exploratory analysis showed higher peripheral blood CXCR3+CD8+ T cell abundance, lower immunosuppressive CD4+ T cell abundance, and higher overlap of clonotypes between tumor-infiltrating T cells and circulating T cells, likely related to preferable response to camrelizumab plus apatinib therapy. Conclusions: In conclusion, the combination of camrelizumab with apatinib showed promising activity and acceptable toxicity in advanced ACC patients who failed previous lines of therapy. Pre-treatment peripheral blood immune cell subsets could be regarded as potential predictors of efficacy. Given the promising clinical activity, the potential of camrelizumab with apatinib as first-line therapy for advanced ACC need further evaluated. Clinical trial information: NCT04318730 .
Health-related quality of life and pain in a phase 3 study of [177Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore).
Authors: Fizazi Karim , Morris Michael J. , Shore Neal D. , Chi Kim N. , Crosby Michael , De Bono Johann S. , Herrmann Ken , Roubaud Guilhem , Nagarajah James , Fleming Mark T. , Lewis Brian E. , Nordquist Luke , Castellano Daniel , Carnahan Natalie , Ghebremariam Samson , Hertelendi Marianna , Sartor Oliver
Published: June 2024

5003

Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [68Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177Lu-PSMA-617 and 6.5 months for ARPI change. 177Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]
Prevalence of HER3 expression in prostate adenocarcinoma and its clinicopathological characteristics.
Authors: Rajendran Rithika , Lap Coen Johannes Gerardus , Estephan Fayez , Liu Shanshan , Subrahmanyam Ramesh , Diao Guoqing , Nava Victor , Jain Maneesh Rajiv
Published: June 2024

5019

Background: Human epidermal growth factor receptor 3 (HER3) has been found upregulated in a wide variety of cancers and has been associated with disease progression and resistance to EGFR-targeted therapies in HER2-positive malignancies. Several studies have reported expression of HER3 in prostate cancer (PCa). Furthermore, concurrent expression of HER2 and HER3 in PCa has been associated with androgen resistance, development of metastatic disease, and less favorable outcomes. However, due to conflicting results, the exact nature of the relationship between HER2 and HER3 in PCa requires further investigation. Methods: 194 patients diagnosed with PCa between 2000-2021 at the Washington DC Veterans Affairs Medical Center who had adequate formalin-fixed paraffin embedded prostate tissue available were selected from our previously published cohort of patients. HER3 immunostaining was performed and independently scored by two pathologists as 0 (absent), 1+ (weak), 2+ (moderate), or 3+ (marked). HER2 immunostaining data and clinical information was retrieved. Statistical analysis included Fisher’s exact test and linear regression models. Results: In our self-identified predominantly African American (85%) patient cohort, a 94% overall prevalence of HER3 positivity (1+, 2+, or 3+) was observed. Notably, the majority of positive patients was found to have HER3 expression of either 2+ (~60%; 116/194) or 3+ (~17%; 33/194). HER3 positivity was associated with a higher PSA ( p=0.023), a higher Grade Group (GG) ( p=0.017), and a higher AJCC disease stage ( p=0.006) at time of diagnosis (Table 1). A significant association was observed between positivity for both HER2 and HER3 ( p=0.031). HER3 positivity independently predicted GG ( p=0.02) and AJCC disease stage ( p=0.01) when adjusted for HER2 positivity. Conclusions: In this predominantly African American cohort, a high prevalence of HER3 positivity was observed across PCa disease stages. Higher expression levels of HER3 were observed in more advanced stages of the disease. Because of the observed efficacy of HER3-antibody drug conjugates in other HER3-expressing malignancies, the high prevalence of HER3 in PCa makes it an attractive therapeutic target that warrants further evaluation.[Table: see text]
Real-world evidence of overall survival (OS) and treatment patterns of patients (pts) with testicular germ cell tumors (GCT) receiving palliative chemotherapy in the United States.
Authors: Feldman Darren R. , Habucky Karen , Gagnon-Sanschagrin Patrick , Maitland Jessica , Boileau Philippe , Yokoji Kana , Guérin Annie , Joseph George
Published: June 2024

5038

Background: Pts with relapsed/refractory (R/R) GCT have a poor prognosis, with only palliative options remaining. Real-world data in this population, particularly around prior salvage strategies with high-dose (HDCT) or conventional-dose chemotherapy (CDCT), are needed to inform future treatment standards. Methods: Adult males with R/R testicular GCT who received palliative chemotherapy between 01/2016 to 03/2023 were identified in the Komodo Research Database Demographics were described on the index date, defined as the date of palliative chemotherapy initiation. OS, defined as the time from index date to death and stratified by prior HDCT exposure, was assessed among pts with 12 months (mos) follow-up time using the Kaplan-Meier method. Additionally, treatment patterns were analyzed in a subgroup of pts with an eligible health plan continuously from diagnosis to index date. Results: Of 57,508 pts with testicular GCT, 248 received palliative chemotherapy, among whom 97 (39.1%) had sufficient claims data to confirm prior exposure to salvage HDCT (+/- CDCT) or only CDCT (57 HDCT; 40 CDCT only). Median (interquartile range [IQR]) age on the index date for these 97 pts was 32 (25-42) years and most had commercial (47.4%) or Medicaid (36.1%) insurance. Observed index palliative regimens included gemcitabine + oxaliplatin (46.4%), oral etoposide (12.4%), and gemcitabine + paclitaxel (12.4%); 24.7% of pts received multiple palliative regimens (median 2, range 2-5). Median (95% confidence interval) OS was 8.0 (6.3-9.7) mos; 7.0 (5.7-9.7) mos for those HDCT exposed, and 9.3 (7.5-22.6) mos for those exposed to CDCT only. The treatment patterns subgroup comprised 51 pts observed for a median of 19.9 (IQR: 15.6-28.8) mos after diagnosis. Median (IQR) time from diagnosis to first-line (1L) chemotherapy was 0.9 (0.5-2.1) mos and to palliative chemotherapy was 12.5 (9.0-16.8) mos. Prior to palliative chemotherapy, 33 pts (64.7%) received salvage chemotherapy, including HDCT (+/- CDCT) in 23 pts (69.7%) and only CDCT in 10 pts (30.3%). Of 18 pts (35.3%) who did not receive salvage chemotherapy prior to palliative chemotherapy, median time from end of 1L chemotherapy to index date was 4.1 (IQR: 2.4-8.0) mos and 13 pts (72.2%) had renal insufficiency. Conclusions: Real-world data was able to capture treatment patterns, palliative chemotherapy use, and outcomes for pts with R/R testicular GCT. Surprisingly, more than 1/3 of pts did not receive a salvage chemotherapy regimen prior to palliative chemotherapy and of those who did, >30% did not receive HDCT. Renal insufficiency may be a major reason for lack of salvage chemotherapy use. These data provide prognostic information and variables influencing poor outcome in this understudied population for whom novel treatments are urgently needed.
Race and association between ADT and adverse events.
Authors: Friedrich Nadine , Janes Jessica L. , Parrish Joshua , De Hoedt Amanda Marie , Tatonetti Nicholas , Freedland Stephen J.
Published: June 2024

5073

Background: Many prior studies have linked androgen deprivation therapy (ADT) for prostate cancer (PC) with adverse events such as cardiac events and osteoporosis. Whether these associations differ by race is unknown. Methods: We performed a retrospective population-level analysis to assess the association between ADT (specifically GnRH agonist) use and time to cardiovascular events, bone fracture, new osteoporosis diagnosis, or time to composite event (i.e., the first of any of cardiovascular, bone fracture, or osteoporosis events) in the Veterans Affairs Health Care System (VA) as a function of race. We identified 790,916 patients from 2001-2021 who were diagnosed with PC and treated with ADT or no ADT. Given small numbers, patients treated with other forms of ADT including bilateral orchiectomy or GnRH antagonists were excluded. Patients were also excluded if they were missing race/ethnicity. Data were stratified by race/ethnicity including: Non-Hispanic White (White) 598,574, Non-Hispanic Black (Black) 145,267, Hispanic 30,139 and Other 16,936. Univariable and multivariable Cox proportional hazards models were used to test the association between ADT as a time-dependent covariate and time to the given event across all patients and as a function of race. Results: On multivariable analysis among all patients, ADT was associated with increased risk of cardiovascular events (HR 1.16, 95% CI 1.15- 1.17, p<0.001), bone fractures (HR 1.59, 95% CI 1.55-1.62, p<0.001), osteoporosis (HR 2.73, 95% CI 2.65-2.80, p<0.001), and composite event (HR 1.29, 95% CI 1.27-1.30, p <0.001). When stratified by race, ADT remained significantly associated with all outcomes in all races (all p<0.001). Compared to White men, among Black men, the HRs for ADT were slightly lower for cardiovascular events (1.09 vs. 1.18), bone fracture (1.35 vs 1.65), and composite event (1.19 vs 1.31), but slightly higher for osteoporosis (3.16 vs 2.64). HRs in Hispanics and Other races were very similar to those in White men. Conclusions: Consistent with many prior studies, we found that ADT was associated with increased risk of cardiovascular events and bone complications. Though risks differed slightly among Black men, overall differences were small. These findings demonstrate that ADT is associated with adverse cardiovascular and bone complications regardless of race. Better means to reduce ADT-associated risks are needed across all races.
Hematologic toxicity in 177lu-PSMA-617 treatment for mCRPC: Unraveling the impact of PSMA PET bone tumor volume (PSMA-bTTV).
Authors: Ghodsi Alireza , Demirci Ridvan Arda , Gulati Roman , Raychaudhuri Ruben , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Nelson Peter , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L. , Iravani Amir
Published: June 2024

5075

Background: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) is a life-prolonging treatment approved by the FDA in metastatic castration-resistant prostate cancer (mCRPC), at a very late stage when there frequently reduced bone marrow reserve. We aim to report the incidence of hematologic toxicity during treatment and potential risk factors in a single-center study. Methods: This retrospective single-institution case series included mCRPC patients who underwent at least one cycle of 177Lu-PSMA-617 treatment between June 2022 and January 2024. Hematological parameters were documented at baseline, 3 weeks after each treatment, and before each subsequent treatment administration. Then, we captured the nadir values for each parameter during treatment. Hematologic toxicities were assessed using the Common Terminology Criteria for Adverse Events v5.0, with Grades 3 and 4 considered significant. Multivariable logistic regression analyses were conducted to investigate the association between hematological adverse events and baseline characteristics including PSMA-bTTV, measured by semi-automatic contouring of the PSMA-expressing whole-body bone metastases on pre-treatment PSMA PET. Results: Our study included 138 mCRPC patients (median age: 73y, prior chemotherapy: 92%, prior radiation: 43.5%, bone involvement: 89.1%), who underwent a median of 3 cycles (IQR: 2-5) of 177Lu-PSMA-617 treatment. At baseline, 8 (5.8%) patients had grade 3 anemia, 2 (1.4%) patients had grade 3 leukopenia, and 1 (0.7%) patient had grade 3 thrombocytopenia. Nadir values during treatment indicated that 23 (16.7%) had grade 3 anemia, 5 (3.6%) had grade 3 leukopenia, and 11 (8%) had grade 3 and 4 thrombocytopenia. Multivariable analysis of predisposing factors for hematologic adverse events showed that the PSMA-bTTV was significantly associated with occurrence of any grade ≥3 hematologic toxicity, anemia, and thrombocytopenia after adjusting for other baseline clinical variables (Table). Conclusions: Over 1 in 5 patients with mCRPC experienced significant hematologic adverse events during treatment with 177Lu-PSMA-617. Bone tumor volume is a possible risk factor for developing significant hematologic toxicity. [Table: see text]
Resources to address challenges in first-line treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC): A discrete choice experiment.
Authors: Loeb Stacy , Agarwal Neeraj , El-Chaar Nader N. , de Ruiter Laura , Kim Janet , Mack Jessica , Bland Christopher S , Rich-Zendel Sarah , Sheldon Jay , Joo Jin Su , Dyson Judith
Published: June 2024

5087

Background: Althoughfirst-line treatment intensification (TI) (i.e., androgen-deprivation therapy with chemotherapy, novel hormonal therapies, or both) is recommended in mCSPC guidelines, it is used in <1/3 of patients. Phase 1 of the IMPLEMENT study used an implementation science approach to identify barriers to and facilitators of TI. Phase 2 of IMPLEMENT aimed to prioritize these factors and identify resources to increase TI. Methods: A discrete choice experiment was developed for 300 US-based physicians (150 oncologists, 150 urologists) who manage mCSPC. It included 6 descriptions of potential resources to help with TI decisions, based on results from Phase 1. Respondents selected from pairs of resource sets the set they perceived as most helpful across 12 scenarios. We analyzed responses using a mixed-effects logistic regression model and calculated a coefficient of helpfulness for each resource to identify those with the strongest impact on physicians’ decisions. Coefficients were required to have a minimum value of zero, as resources would be optional. Results: Overall, physicians preferred decision support tools and databases of post-treatment options. Urologists found decision support tools most beneficial (coefficient of helpfulness 3.27; 95% CI 2.90-3.64), while oncologists preferred post-treatment databases (2.58; 95% CI 2.29-2.89) and clinical trial summaries (2.41; 95% CI 2.13-2.69). Tools to reduce administrative burden and information on outcomes of earlier vs later TI were not considered as helpful compared to other resources and across specialties. Conclusions: There were key differences between specialties in the helpfulness of resources, indicating substantial variability in clinical practice needs. These findings provide a clear path to develop concrete, specialty-tailored tools to increase guideline-concordant treatment of mCSPC. [Table: see text]
Impact of pre-treatment MRI capsular involvement and extraprostatic extension on metastasis free and overall survival in localized prostate cancer.
Authors: Kumar Abhishek , LaBella Dominic , Snider Michael , Acklin-Wehnert Scarlett , Gupta Rajan T. , Salama Joseph Kamel , Boyer Matthew J
Published: June 2024

5097

Background: Multiparametric magnetic resonance imaging (mpMRI) is not currently included in prostate cancer (PC) staging. The purpose of this study was to test the association between mpMRI detected prostate capsule involvement and extraprostatic extension (EPE) with metastasis free survival (MFS) and overall survival (OS) in patients treated for localized PC. Methods: Patients treated for localized PC between 2000-2021 from the Veterans Affairs Prostate Data Core having an mpMRI prior to definitive treatment were identified. MRI reports were assessed for minor or significant capsule abutment (defined as greater than or equal to 1.5 cm of capsule contact or radiologist’s mention of long segment abutment), extracapsular extension (ECE), seminal vesicle invasion (SVI), or adjacent organ invasion (OI). mpMRI findings' impact on MFS by multivariable Fine-Gray competing-risks regression and OS by Cox regression were assessed. Results: Overall, 2,933 patients were included. Most pre-treatment mpMRIs (85%) occurred after 2016. 1,238 (42%) patients were Black. 569 (19%) patients had palpable disease. Median follow-up was 5 years. The 5-year cumulative incidence of metastasis was 10% (95% confidence interval (CI) 9-11%) and death was 7% (95% CI 6-9%). There were 643 (22%) patients with minor capsule abutment, 212 (7%) with significant capsule abutment, 281 (10%) with ECE, 103 (4%) with SVI, and 25 (1%) with OI. After controlling for age, race, prostate specific antigen level, grade group, clinical tumor stage, and treatment, the presence of significant capsule abutment, ECE, SVI, and OI were independently associated with MFS, but minor capsule abutment was not. On multivariable analysis controlling for the same factors, EPE (ECE, SVI, or OI) was associated with worse OS. Conclusions: In a modern, real-world cohort of localized PC patients from the largest integrated health system in the United States, significant capsule abutment and EPE on mpMRI are independently prognostic of MFS, but minor capsular abutment is not. EPE is associated with inferior OS. Given its independent prognostic value for MFS and association with OS, mpMRI should be more widely available to PC patients. Studies are ongoing to define its role as a standard staging tool. [Table: see text]
A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.
Authors: Green Angela , Zhou Qin , Iasonos Alexia , Zammarrelli William , Weigelt Britta , Ellenson Lora H , Chhetri-Long Rashmi , Shah Pooja , Hom Vania , Erinjeri Joseph P. , Petkovska Iva , Chandarlapaty Sarat , Cohen Seth M. , Grisham Rachel N. , Konner Jason A. , Rubinstein Maria M , Tew William P. , Troso-Sandoval Tiffany A. , Aghajanian Carol , Makker Vicky
Published: June 2024

5511

Background: Inhibition of the Cyclin D-Cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Elevated CDK4 expression is observed in 34–77% of endometrioid endometrial cancers (ECs) and is an early event of neoplastic transformation. Responses to endocrine monotherapy in advanced or recurrent EC are suboptimal and short-lived. We hypothesized that CDK4/6 inhibition with abemaciclib combined with fulvestrant is a promising strategy to improve outcomes with endocrine therapy in patients (pts) with advanced or recurrent hormone receptor-positive EC. Methods: This was an investigator-initiated, open label, single arm phase II study in pts with advanced or recurrent EC. Eligibility criteria included age ≥18 years, estrogen receptor or progesterone receptor expression ≥ 1% by immunohistochemistry, measurable disease, ≤ 2 prior lines of chemotherapy, and ≤ 1 prior line of hormonal therapy. All histologies were eligible except carcinosarcoma. Mixed histologies required ≥ 95% endometrioid component. Pts received fulvestrant 500 mg intramuscularly monthly with an initial 2-week loading dose and abemaciclib 150 mg orally twice daily until disease progression or prohibitive toxicity. Primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1. Results: At data cutoff (October 7, 2023), 27 pts initiated protocol therapy and 25 pts were evaluable for efficacy. 24 pts (89%) had tumors with endometrioid histology. 9 pts (33%) had prior hormonal therapy and 26 pts (96%) had ≥1 prior line of chemotherapy. 11 pts achieved a partial response resulting in an ORR of 44% (90% CI, 27.0% to 62.1%). The median duration of response, among pts that experienced a response, was 15.6 months (90% CI, 7.2 – nonestimable (NE)). All responses were in grade 1 or 2 endometrioid ECs. 10 out of 11 responses (91%) were in pts with copy number low/no specific molecular profile ECs, while 1 response (9%) was in a patient with microsatellite instability-high EC. Median PFS was 9.0 months (90% CI 1.8 to 20.4) and median OS was 37.8 months (90% CI 16.3 to NE). Most common ≥ grade 3 treatment related adverse events were neutropenia (22%) and anemia (19%). Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses observed in pts with advanced or recurrent EC; a phase 3 trial is planned. Clinical trial information: NCT03643510 .