bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross-sectional study reporting concussion exposure, assessment and management in Western Australian general practice
Authors: Thomas Elizabeth , Chih HuiJun , Gabbe Belinda , Fitzgerald Melinda , Cowen Gill
Published: March 2021

Background

General Practitioners (GPs) may be called upon to assess patients who have sustained a concussion despite limited information being available at this assessment. Information relating to how concussion is actually being assessed and managed in General Practice is scarce. This study aimed to identify characteristics of current Western Australian (WA) GP exposure to patients with concussion, factors associated with GPs’ knowledge of concussion, confidence of GPs in diagnosing and managing patients with concussion, typical referral practices and familiarity of GPs with guidelines.

Methods

In this cross-sectional study, GPs in WA were recruited via the RACGP WA newsletter and shareGP and the consented GPs completed an electronic survey. Associations were performed using Chi-squared tests or Fisher’s Exact test.

Results

Sixty-six GPs in WA responded to the survey (response rate = 1.7%). Demographics, usual practice, knowledge, confidence, identification of prolonged recovery as well as guideline and resource awareness of GPs who practised in regional and metropolitan areas were comparable (p > 0.05). Characteristics of GPs were similar between those who identified all symptoms of concussion and distractors correctly and those who did not (p > 0.05). However, 84% of the respondents who had never heard of concussion guidelines were less likely to answer all symptoms and distractors correctly (p = 0.039). Whilst 78% of the GPs who were confident in their diagnoses had heard of guidelines (p = 0.029), confidence in managing concussion was not significantly associated with GPs exposure to guidelines. It should be noted that none of the respondents correctly identified signs of concussion and excluded the distractors.

Conclusions

Knowledge surrounding concussion guidelines, diagnosis and management varied across GPs in WA. Promotion of available concussion guidelines may assist GPs who lack confidence in making a diagnosis. The lack of association between GPs exposure to guidelines and confidence managing concussion highlights that concussion management may be an area where GPs could benefit from additional education and support.
Ten-day bismuth-containing quadruple therapy versus 7-day proton pump inhibitor-clarithromycin containing triple therapy as first-line empirical therapy for the Helicobacter pylori infection in Korea: a randomized open-label trial
Authors: Kim Young-Il , Lee Jong Yeul , Kim Chan Gyoo , Park Boram , Park Jin Young , Choi Il Ju
Published: March 2021

Background

This randomized, open-label trial aimed to compare the efficacy of 10-day bismuth-containing quadruple therapy (BQT) with 7-day proton-pump inhibitor-clarithromycin containing standard triple therapy (STT) as an empirical first-lineHelicobacter pyloritherapy.

Methods

Participants withH. pyloriinfection were randomly assigned to either 10-day BQT (daily doses of bismuth 300 mg, four times; lansoprazole 30 mg, twice; metronidazole 500 mg, three times; and tetracycline 500 mg, four times) or 7-day STT (lansoprazole 30 mg; amoxicillin 1,000 mg; and clarithromycin 500 mg; each given twice daily). Participants who failed initial therapy were crossed over to the alternative treatment regimen. Primary outcome was the eradication rates of first-line treatment by intention-to-treat analysis.

Results

Study participants (n = 352) were randomized to receive either 10-day BQT (n = 175) or 7-day STT (n = 177). The BQT-group achieved a significantly higher eradication rate than the STT-group in the intention-to-treat analysis (74.3% vs 57.1%, respectively;P = 0.001), modified intention-to-analysis (87.2% [130/149] vs 68.7% [101/147], respectively;P < 0.001) and per-protocol analysis (92.9% [105/113] vs 70.1% [94/134], respectively;P < 0.001). Although there was no serious adverse event, the compliance was lower with BQT than STT as a higher proportion of participants in the BQT-group discontinued therapy because of adverse events than those in the STT-group (23.1% vs 9.1%, respectively;P = 0.001)

Conclusions

Ten-day BQT had higher eradication rates compared to that of the 7-day STT as an empirical first-line treatment forH. pylorieradication in Korea.

Trial registration: ClinicalTrials.gov, NCT02557932. Registered 23 September 2015,https://clinicaltrials.gov/ct2/show/NCT02557932?term=NCT02557932&draw=2&rank=1.
Delirium in older patients undergoing aortic valve replacement: incidence, predictors, and cognitive prognosis
Authors: Humbert Marc , Büla Christophe J. , Muller Olivier , Krief Hélène , Monney Pierre
Published: March 2021

Background

Transcatheter aortic valve replacement is increasingly performed in frail older patients who were previously ineligible for a standard surgical procedure. The objectives of this study are to determine delirium incidence, predictors, and relationship with cognitive performance at 3-month follow-up in older patients undergoing aortic valve replacement (AVR).

Methods

Patients (N = 93) aged 70 years and older, undergoing transcatheter (TAVR, N = 66) or surgical (SAVR, N = 27) aortic valve replacement in an academic medical center were enrolled in this prospective cohort study. Delirium was assessed using the Confusion Assessment Method (CAM) on postoperative days 1, 2, 3, and 7. Data on patients’ socio-demographics, functional status (including instrumental activities of daily living (IADL), and surgical risk scores (including Society of Thoracic Surgeons (STS) risk score), were collected at baseline. Cognitive status was assessed with the Mini-Mental Status Exam (MMSE) and the Clock Drawing Test (CDT) at baseline and 3 months after AVR.

Results

Delirium occurred in 21 (23%) patients, within the first three postoperative days in 95% (20/21) of the cases. Delirium incidence was lower in TAVR (13/66 = 20%) than SAVR (8/27 = 30%) patients, but this difference was not statistically significant (p = .298). Patients with delirium had lower baseline cognitive performance (median MMSE score 27.0 ± 3.0 vs 28.0 ± 3.0, p = .029), lower performance in IADL (7.0 vs 8.0, p = .038), and higher STS risk scores (4.7 ± 2.7 vs 2.9 ± 2.3, p = .020). In multivariate analyses, patients with intermediate (score > 3 to ≤8) and high (score > 8) STS risk scores had 4.3 (95%CI 1.2–15.1, p = .025) and 16.5 (95%CI 2.0–138.2, p = .010), respectively, higher odds of incident delirium compared to patients with low (score ≤ 3) STS risk scores. At 3-month follow-up (N = 77), patients with delirium still had lower MMSE score (27.0 ± 8.0 vs 28.0 ± 2.0, p = .007) but this difference did not remain significant once adjusting for baseline MMSE (β-coefficient 1.11, 95%CI [− 3.03–0.80], p = .248).

Conclusions

Delirium occurred in about one in five older patients undergoing AVR, almost essentially within the first three postoperative days. Beside cognitive performance, STS risk score could enhance the identification of high-risk older patients to better target preventative interventions.
Patients with infective endocarditis and history of injection drug use in a Swedish referral hospital during 10 years
Authors: Damlin Anna , Westling Katarina
Published: March 2021

Background

Patients with injection drug use (IDU) have increased risk of developing infective endocarditis (IE). Previous studies have reported recurrent IE, increased duration of hospital stay, poor adherence and compliance as well as higher mortality and worse outcomes after surgery in the IDU-IE patient group. Further studies are needed to provide a basis for optimized care and prevention of readmissions in this population. This study aims to describe the clinical characteristics and outcomes among patients with IDU-IE.

Methods

Data of adults with IDU-IE and non-IDU-IE, treated between 2008 and 2017 at the Karolinska University Hospital in Stockholm were obtained from the Swedish National Registry of Infective Endocarditis. Clinical characteristics, microbiological results, treatment durations, results from echocardiography and in-hospital mortality were compared between the groups.

Results

Of the total 522 patients, 165 (32%) had IDU-IE. Patients with IDU-IE were younger than the patients with non-IDU-IE (mean age IDU-IE: 41.6 years, SD 11.9 years; non-IDU-IE: 64.3 years, SD 16.4 years; P <  0.01). No difference in distribution of gender was observed, 33% were females in both the IDU-IE and the non-IDU-IE group. History of previous IE (IDU-IE: n = 49, 30%; non-IDU-IE: n = 34, 10%; P <  0.01) and vascular phenomena (IDU-IE: n = 101, 61%; non-IDU-IE: n = 120, 34%; P <  0.01) were more common among patients with IDU-IE while prosthetic heart valves (IDU-IE: n = 12, 7%; non-IDU-IE: n = 83, 23%; P <  0.01) and known valvular disease (IDU-IE: n = 3, 2%; non-IDU-IE: n = 78, 22%; P <  0.01) were more common among patients with non-IDU-IE. Aetiology of Staphylococcus aureus (IDU-IE: n = 123, 75%; non-IDU-IE: n = 118, 33%; P <  0.01) as well as tricuspid (IDU-IE: n = 91, 55%; non-IDU-IE: n = 23, 6%; P <  0.01) or pulmonary valve vegetations (IDU-IE: n = 7, 4%; non-IDU-IE: n = 2, 1%; P <  0.01) were more common in the IDU-IE group. The overall incidence of IDU-IE decreased during the study period, while the incidence of definite IE increased (P <  0.01).

Conclusions

This study presents that patients with IDU-IE were younger, less frequently treated with surgery and had higher prevalence of vascular phenomena and history of previous IE, aspects that are important for improved management of this population.
Characteristics of interval gastric neoplasms detected within two years after negative screening endoscopy among Koreans
Authors: Lim Joo Hyun , Song Ji Hyun , Chung Su Jin , Chung Goh Eun , Kim Joo Sung
Published: March 2021

Background

In Korea, where gastric cancer is highly prevalent, biennial endoscopy is recommended among individuals over 40. Even under regular screening, some are still diagnosed at advanced stages. We aimed to identify characteristics of interval gastric neoplasms (IGNs) with rapid progression.

Results

Newly-diagnosed gastric neoplasms detected in screening endoscopy between January 2004 and May 2016 were reviewed. Among them, those who had previous endoscopy within 2 years were enrolled. Endoscopic findings, family history of gastric cancer, smoking, and H. pylori status were analysed. Totally, 297 IGN cases were enrolled. Among them, 246 were endoscopically treatable IGN (ET-IGN) and 51 were endoscopically untreatable IGNs (EUT-IGN) by the expanded criteria for endoscopic submucosal dissection. Among EUT-IGNs, 78% were undifferentiated cancers (40/51) and 33% showed submucosal invasion (13/40). They were median 2.0 cm in size and more commonly located in the proximal stomach than ET-IGNs (70.6% vs. 41.9%, p < 0.001). EUT-IGN was independently related with age < 60 (OR, 2.09; 95%CI, 1.03–4.26, p = 0.042), H. pylori (OR, 2.81; 95%CI, 1.20–6.63, p = 0.018), and absent/mild gastric atrophy (OR, 2.67; 95%CI, 1.25–5.72, p = 0.011). Overall and disease-specific survival were not significantly different between the two groups, however EUT-IGN tended to have short disease-specific survival (overall survival, p = 0.143; disease-specific survival, p = 0.083).

Conclusions

Uniform screening endoscopy with two-year interval seems not enough for rapid-growing gastric neoplasms, such as undifferentiated cancers. They tended to develop in adults younger than 60 with H. pylori infection without severe gastric atrophy. More meticulous screening, especially for proximal lesions is warranted for adults younger than 60 with H. pylori infection before development of gastric atrophy.
Factors associated with ocular surface epithelial damage in patients with primary Sjögren’s syndrome
Authors: Kim Ji Eun , Kim Na Rae , Chin Hee Seung , Seo Kyoung Yul , Kim Tae-im , Jung Ji Won
Published: March 2021

Background

The aim of this study was to evaluate the effects of systemic parameters, laboratory findings, oral parameters, and other ocular surface parameters on ocular surface epithelial damage in patients with primary Sjögren’s syndrome (pSS).

Methods

A total of 82 dry eye disease (DED) patients with pSS were enrolled in this study. Ocular surface epithelial damage was measured by ocular staining score (OSS). Systemic parameters, laboratory findings including serologic markers, oral parameters, and other ocular surface parameters were collected. Other ocular surface parameter assessments such as the Schirmer’s test, fluorescein tear breakup time, meibomian gland examinations, noninvasive keratographic tear film break-up time measurements using the Keratograph® 5 M were performed, and the Ocular Surface Disease Index was determined.

Results

In a multivariate analysis, decreased age and increased duration of pSS were significantly related to increased logarithm-transformed OSS (β = -0.011, P = 0.043 and β = 0.003, P = 0.008). Among the ocular surface parameters, decreased fluorescein tear breakup time and increased MGD grade were significantly associated with increased logarithm-transformed OSS (β = -0.183, P < 0.001 and β = 0.192, P = 0.049).

Conclusions

Ocular surface epithelial damage in patients with pSS was associated with young age, long duration of disease, unstable tear film, and decreased meibomian gland function.
A cross-sectional study of characteristics of bicyclist upper and lower extremity injuries in bicycle-vehicle crashes in Ohio, United States, 2013–2017
Authors: Makara Jodie , Shen Sijun , Nwosu Ann , Arnold William , Smith Gary , Zhu Motao
Published: March 2021

Background

Extremity injury is one of the most common injury types for bicyclists. Extremity injury can lead to long-term disability and contribute to adverse health-related quality of life and prolonged absence from work.

Objectives

The objectives of our study were to identify crash factors associated with bicyclist upper and lower extremity injury and characterize type of extremity injury by bicyclist age category.

Methods

We linked the 2013–2017 Ohio police accident report and hospital databases. The logistic regression model was used to model the odds of sustaining upper or lower extremity injury among bicyclists involved in bicycle-vehicle crashes. Bicyclist upper and lower extremity injury were further described by the detailed injured body regions (e.g., forearm and elbow or lower leg) and the nature of injury (e.g., superficial or fracture).

Results

Bicyclists 65 years or older had higher odds (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.03–2.08) of sustaining upper extremity injury, bicyclists aged 3–14 years (OR = 1.34, 95% CI: 1.09–1.66) and 15–24 years (OR = 1.24, 95% CI: 1.03–1.49) had higher odds of sustaining lower extremity injury, compared to bicyclists 25–44 years old. In addition, colder weather, bicyclist sex, and intersection-related crashes were associated with bicyclists’ odds of sustaining upper or lower extremity injury. Compared to individuals under 65 years old, bicyclists 65 years or older had a higher percentage of injury to the wrist, hand and finger, or knee. Bicyclists aged 65 years or older also had a higher percentage of fractures.

Conclusions

Our study has identified important factors that were associated with bicyclists’ odds of sustaining an extremity injury. Based on these findings, targeted educational efforts and interventions can be implemented to prevent bicyclists from these injuries.
Is there a need for a clear advice? A retrospective comparative analysis of ethics consultations with and without recommendations in a maximum-care university hospital
Authors: Schmitz Dagmar , Groß Dominik , Pauli Roman
Published: March 2021

Background

The theory and practice of ethics consultations (ECs) in health care are still characterized by many controversies, including, for example, the practice of giving recommendations. These controversies are complicated by an astonishing lack of evidence in the whole field. It is not clear how often a recommendation is issued in ethics consultations and when and why this step is taken. Especially in a facilitation model in which giving recommendations is optional, more data would be helpful to evaluate daily practice, ensure that this practice is in line with the overarching goals of this approach and support the development of standards.

Methods

We analyzed all consultations requested from an EC service working under a facilitation approach at a maximum-care university hospital in Germany over a period of more than 10 years. Our aim was to better understand why—and under what circumstances—some consultation requests result in a recommendation, whereas others can be sufficiently addressed solely by facilitated meetings. We especially wanted to know when and why clients felt the need for clear advice from the EC service while in other cases they did not. We compared ethics consultations in terms of the differences between cases with and without recommendations issued by the ethics consultants using χ2difference tests and Welch’s t-test.

Results

A total of 243 ECs were carried out between September 2008 and December 2019. In approximately half of the cases, a recommendation was given. All recommendations were issued upon the request of clients. When physicians asked for an EC, the consultation was significantly more likely to result in a recommendation than when the EC was requested by any other party. ECs in cases on wards with ethics rounds resulted in comparably fewer recommendations than those in wards without ethics rounds. When interpersonal conflicts were part of the problem or relatives were present in the meeting, clients less frequently asked for a recommendation.

Conclusion

From the client’s point of view, there does not seem to be only one “right” way to provide ethics consultations, but rather several. While facilitated meetings are obviously appreciated by clients, there also seem to be situations in which a recommendation is desired (especially by physicians). Further empirical and theoretical research is needed to validate our single-center results and re-evaluate the role of recommendations in ethics consultations.
Fermentative production of enantiopure (S)-linalool using a metabolically engineered Pantoea ananatis
Authors: Nitta Nobuhisa , Tajima Yoshinori , Yamamoto Yoko , Moriya Mika , Matsudaira Akiko , Hoshino Yasushi , Nishio Yousuke , Usuda Yoshihiro
Published: March 2021

Background

Linalool, an acyclic monoterpene alcohol, is extensively used in the flavor and fragrance industries and exists as two enantiomers, (S)- and (R)-linalool, which have different odors and biological properties. Linalool extraction from natural plant tissues suffers from low product yield. Although linalool can also be chemically synthesized, its enantioselective production is difficult. Microbial production of terpenes has recently emerged as a novel, environmental-friendly alternative. Stereoselective production can also be achieved using this approach via enzymatic reactions. We previously succeeded in producing enantiopure (S)-linalool using a metabolically engineered Pantoea ananatis, a member of the Enterobacteriaceae family of bacteria, via the heterologous mevalonate pathway with the highest linalool titer ever reported from engineered microbes.

Results

Here, we genetically modified a previously developed P. ananatis strain expressing the (S)-linalool synthase (AaLINS) from Actinidia arguta to further improve (S)-linalool production. AaLINS was mostly expressed as an insoluble form in P. ananatis; its soluble expression level was increased by N-terminal fusion of a halophilic β-lactamase from Chromohalobacter sp. 560 with hexahistidine. Furthermore, in combination with elevation of the precursor supply via the mevalonate pathway, the (S)-linalool titer was increased approximately 1.4-fold (4.7 ± 0.3 g/L) in comparison with the original strain (3.4 ± 0.2 g/L) in test-tube cultivation with an aqueous-organic biphasic fermentation system using isopropyl myristate as the organic solvent for in situ extraction of cytotoxic and semi-volatile (S)-linalool. The most productive strain, IP04S/pBLAAaLINS-ispA*, produced 10.9 g/L of (S)-linalool in “dual-phase” fed-batch fermentation, which was divided into a growth-phase and a subsequent production-phase. Thus far, this is the highest reported titer in the production of not only linalool but also all monoterpenes using microbes.

Conclusions

This study demonstrates the potential of our metabolically engineered P. ananatis strain as a platform for economically feasible (S)-linalool production and provides insights into the stereoselective production of terpenes with high efficiency. This system is an environmentally friendly and economically valuable (S)-linalool production alternative. Mass production of enantiopure (S)-linalool can also lead to accurate assessment of its biological properties by providing an enantiopure substrate for study.
Prognostic biomarker TUBA1C is correlated to immune cell infiltration in the tumor microenvironment of lung adenocarcinoma
Authors: Bian Tingting , Zheng Miaosen , Jiang Daishan , Liu Jian , Sun Hui , Li Xiaoli , Liu Lei , Zhang Jianguo , Liu Yifei
Published: March 2021

Background

TUBA1C is a microtubule component that is involved in a variety of cancers. Our main objective was to investigate TUBA1C expression, its prognostic value, its potential biological functions, and its impact on the immune system of patients with lung adenocarcinoma (LUAD).

Methods

The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA) and Immunohistochemistry Analysis were used to analyze TUBA1C expression, its clinicopathology, overall survival (OS), and disease-free survival (DFS) in LUAD patients. We also determined the correlation between TUBA1C and tumor-infiltrating immune cells (TIICs) by using CIBERSORT and GEPIA databases. To determine the expression of TUBA1C in LUAD, we analyzed a collection of immune infiltration levels and cumulative survival of LUAD tissues in TIMER database. By using UALCAN, STRING, and GeneMANIA databases, we investigated the protein-coding genes related to TUBA1C and its co-expression genes in LUAD tissues. Gene set enrichment analysis (GSEA) was performed by using the TCGA dataset.

Results

The mRNA and the protein expression of TUBA1C were found to be up-regulated in LUAD tissues. The univariate analysis indicated that an increased expression of TUBA1C was significantly correlated to the following parameters: age, stage, and lymph node metastasis. An over-expression of TUBA1C was associated with a poor prognosis of LUAD. In TIMER and CIBERSORT databases, we found that TUBA1C is correlated with 13 types of TIICs: activated B cell, activated CD4 T cell, central memory CD4 T cell, effector memory CD8 T cell, eosinophils, immature B cell, gamma-delta T cell, immature dendritic cell, mast cell, memory B cell, natural killer T cell, regulatory T cell, and type 2T helper cell. By performing GSEA, we found that TUBA1C is closely correlated to cell cycle, p53 signaling pathway, glycolysis, and gluconeogenesis.

Conclusions

Our findings indicate that TUBA1C is associated with TIICs in tumor microenvironment. Therefore, it serves as a novel prognostic biomarker and a target for future treatment methods of LUAD.
Genetic diversity and natural selection on the thrombospondin-related adhesive protein (TRAP) gene of Plasmodium falciparum on Bioko Island, Equatorial Guinea and global comparative analysis
Authors: Lin Li-Yun , Huang Hui-Ying , Liang Xue-Yan , Xie Dong-De , Chen Jiang-Tao , Wei Hua-Gui , Huang Wei-Yi , Ehapo Carlos Salas , Eyi Urbano Monsuy , Li Jian , Wang Jun-Li , Zheng Yu-Zhong , Zha Guang-Cai , Wang Yu-Ling , Chen Wei-Zhong , Liu Xiang-Zhi , Mo Huan-Tong , Chen Xin-Yao , Lin Min
Published: March 2021

Background

Thrombospondin-related adhesive protein (TRAP) is a transmembrane protein that plays a crucial role during the invasion of Plasmodium falciparum into liver cells. As a potential malaria vaccine candidate, the genetic diversity and natural selection of PfTRAP was assessed and the global PfTRAP polymorphism pattern was described.

Methods

153 blood spot samples from Bioko malaria patients were collected during 2016–2018 and the target TRAP gene was amplified. Together with the sequences from database, nucleotide diversity and natural selection analysis, and the structural prediction were preformed using bioinformatical tools.

Results

A total of 119 Bioko PfTRAP sequences were amplified successfully. On Bioko Island, PfTRAP shows its high degree of genetic diversity and heterogeneity, with π value for 0.01046 and Hd for 0.99. The value of dN–dS (6.2231, p < 0.05) hinted at natural selection of PfTRAP on Bioko Island. Globally, the African PfTRAPs showed more diverse than the Asian ones, and significant genetic differentiation was discovered by the fixation index between African and Asian countries (Fst > 0.15, p < 0.05). 667 Asian isolates clustered in 136 haplotypes and 739 African isolates clustered in 528 haplotypes by network analysis. The mutations I116T, L221I, Y128F, G228V and P299S were predicted as probably damaging by PolyPhen online service, while mutations L49V, R285G, R285S, P299S and K421N would lead to a significant increase of free energy difference (ΔΔG > 1) indicated a destabilization of protein structure.

Conclusions

Evidences in the present investigation supported that PfTRAP gene from Bioko Island and other malaria endemic countries is highly polymorphic (especially at T cell epitopes), which provided the genetic information background for developing an PfTRAP-based universal effective vaccine. Moreover, some mutations have been shown to be detrimental to the protein structure or function and deserve further study and continuous monitoring.
Osteosarcoma: a review of current and future therapeutic approaches
Authors: Zhao Xin , Wu Qirui , Gong Xiuqing , Liu Jinfeng , Ma Yujie
Published: March 2021

Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.
Correction to: Classification of topography for ground vulnerability assessment of alluvial plains and mountains of Japan using 30 m DEM
Authors: Iwahashi Junko , Yamazaki Dai , Nakano Takayuki , Endo Ryo
Published: March 2021

An amendment to this paper has been published and can be accessed via the original article.
Transarterial chemoembolisation in patients with hepatocellular carcinoma: low-dose doxorubicin reduces post-embolisation syndrome without affecting survival—prospective interventional study
Authors: Bessar Ahmed A. , Farag Ahmed , Abdel Monem Sameh M. , Wadea Fady M. , Shaker Shady E. , Ebada Mahmoud Ahmed , Bessar Manar A.
Published: March 2021

Background

No chemotherapeutic agents have been standardised for transarterial chemoembolisation (TACE). In particular, doxorubicin has no defined optimal dosage in TACE procedures. We compared low versus currently used dose of doxorubicin for TACE in patients with hepatocellular carcinoma (HCC) in terms of severity of post-embolisation syndrome (PES) and overall survival (OS).

Methods

From October 2014 to March 2018, we enrolled patients with primary HCC scheduled for TACE. Patients were randomised to receive 50 mg (group A) or 100 mg (group B) of doxorubicin. Outcomes were the rate of patients with PES; free-time-to-PES; changes in laboratory results; tumour response at 1, 3, and 6 months after TACE; and overall survival.

Results

Twenty-eight patients (24 males, 4 females) were enrolled, aged 58.9 ± 6.8 years (mean ± standard deviation). Fifteen of them palliated with 50 mg (group A) and 13 with 100 mg (group B) of doxorubicin for a total of 68 TACE procedures (of 28 patients who had repeated TACE procedures). Visual analogue scale (VAS) and duration of pain were significantly differently lower in group A than in group B (p < 0.001). The median duration of fever was shorter in group A than in group B (p = 0.003). No significant differences between both groups were observed for tumour response to TACE and OS. The doxorubicin dose was significantly correlated with duration of pain, fever, and VAS score.

Conclusion

A lower dose of doxorubicin (50 mg) was associated with fewer PES symptoms compared with 100 mg, without effects on tumour response nor OS.
Value for money in genitourinary oncology.
Authors: O Reilly David Edward , McLaughlin Ronan Andrew , DeFrein Anne-Marie , Ronayne Cian , Macanovic Bojan , McMahon David , Power Derek Gerard , Bambury Richard Martin , Collins Dearbhaile Catherine
Published: March 2021

1

Background: Innovation in the treatment of genitourinary (GU) malignancies is accelerating, however, many of these new treatments are often not available for patients. We sought to investigate patient access, cost and value of new systemic anti-cancer compounds (SACTs) in GU oncology. We compared the US and Europe with a focus on the United Kingdom (UK) and the Republic of Ireland (IRL). Methods: Data on licensing and reimbursement decisions was collected on SACTs approved for GU oncology between 01/01/2010 to 09/01/2020. Overall survival (OS) benefit, progression free survival (PFS) benefit and cost of therapy were included in our analysis. Results: There were 29 regimens/indications approved by the Federal Drug Agency (FDA) for GU malignancies between 2010 and 2020. The majority of these (21/29, 72%) were also approved by the European Medicines Agency (EMA). Nearly all regimens/indications were approved by the FDA prior to the EMA (27/29, 93%), with a median time to EMA approval of 4 months (SD = 6, range -6 to 17). Only a minority of these regimens/indications are reimbursed by the public health systems in the UK (12/29, 41%) and IRL (6/29, 21%). Following EMA approval, public reimbursement of these regimens in the UK and IRL is often delayed with a median time of 8 months (+/- 6.3, range 4 - 21) and 11.5 months (+/- 12.5, range 0 - 33) respectively. Approximately half (15/29, 52%) of all reimbursed regimens/indications have demonstrated an overall survival benefit for patients. Androgen signalling inhibitors (ASIs) are more likely to have a proven OS benefit and had a lower mean cost than non-ASI regimens (See Table). A significant minority of regimens/indications (6/29, 21%) have demonstrated neither an OS or PFS benefit. The median price per month (USA list price) was $15,086 +/- $7,019. Regimens with a proven OS benefit were not more expensive than those without ($14,229 +/- $6,466 versus $16,004 +/- $7,704). There was no significant correlation between the length of OS benefit and the cost of regimens (Pearson’s Correlation Coefficient = -2.72, p = 0.445). Conclusions: Patients in the UK and IRL experience clinically significant delays in accessing FDA approved regimens in GU oncology. Only 52% of these regimens have a proven OS benefit. In our study, ASI regimens are cheaper and more effective than non-ASI regimens. There is no association between overall survival benefit and list prices in the USA. We need to radically overhaul licensing and funding of SACTs in GU oncology to ensure continued access for patients to effective medicines. [Table: see text]
SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic,castrate-refractory prostate cancer (mCRPC)—A phase I/randomized phase II study by the United Kingdom National Cancer Research Institute Prostate Group.
Authors: Jones Robert J. , Bahl Amit , De Bono Johann S. , Ralph Christy , Elliott Tony , Robinson Angus , Westbury Charlotte , Birtle Alison Jane , Staffurth John Nicholas , Protheroe Andrew , Venugopal Balaji , Thomson Fiona , Pou Chantevy , Morris Karen , Tugwood Jonathan , Divers Laura , Hopkins Carol , McCartney Elaine , Kelly Caroline , Crabb Simon J.
Published: March 2021

107

Background: Saracatinib is an orally-available, highly selective inhibitor of Abl and Src family members. It is an ATP-competitive tyrosine kinase inhibitor. Preclinical data suggested that the combination of a Src kinase inhibitor and docetaxel is synergistic, and Src kinase activity was also implicated in the bone’s metabolic response to cancer metastases. Methods: Patients with mCRPC were initially enrolled in an open-label, dose escalation phase I trial of oral saracatinib (cohorts of 50mg, 125mg and 175mg daily) with docetaxel (75mg/m2) in a 3+3 design. Subsequent patients were randomised 1:1 between saracatinib 175mg and placebo once daily. Pharmacokinetics (PK) of docetaxel were explored in phase I to exclude significant drug-drug interaction. The primary endpoint of phase II was biochemical or radiographic progression free survival (PFS). Secondary endpoints included overall survival (OS), safety and tolerability. Changes in circulating tumour cell (CTC) counts were also measured. The phase II was designed with a 1-sided alpha of 0.2 with 90% power to detect a hazard ratio (HR) for PFS of 0.67. Results: 10 patients were enrolled in phase I and 142 in the randomised phase II. No dose limiting toxicities or PK interactions were observed and the recommended dose for phase II was 175mg saracatinib daily and 75mg/m2docetaxel every 21 days. In phase II, the HR for PFS was 1.35 (80% confidence interval (CI) 1.07 to 1.70). The HR for OS was 1.42 (1.08 – 1.81). 41/71 and 29/71 experienced treatment related toxicities of grade 3 or above in the saracatinib and placebo arms respectively. 10/19 (53%) and 14/27 (52%) evaluable patients demonstrated a reduction in CTCs from ≥5 to < 5 /7.5ml blood at 6 weeks after starting saracatinib and placebo respectively. Conclusions: Saracatinib, in combination with docetaxel, adds toxicity and not efficacy in mCRPC. This combination should not be developed further in combination with docetaxel in the treatment of mCRPC. Clinical trial information: ISRCTN22566729.
A phase I/II study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): Dose escalation results.
Authors: Lau Brandon , Crumbaker Megan , Yam Andrew On Wah , Marastoni Stefano , Luckhurst Mathew , O'Grady Aaron , Wouters Brad , Joshua Anthony M.
Published: March 2021

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Background: Preclinical data show hydroxychloroquine (HCQ) and suba-itraconazole (SI) together enhance prostate cancer cell death. The proposed mechanism is lysosome dysfunction including sequestration of cholesterol in endosomes and inhibition of gogi-lyosome trafficking. HCQ/SI could delay androgen deprivation therapy (ADT) and its associated morbidity in men with biochemical relapse of prostate cancer. In this phase I/II study, maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of HCQ/SI was investigated in such patients. Methods: Patients received escalating doses of HCQ with fixed SI 150mg BD in rolling 6 design. This will be followed by a planned phase II Simon 2-stage cohort expansion. Results: Eleven men were treated with HCQ/SI. Median age 73 (range 69-77), baseline PSA 4.4 µg/L (1.6-22.4) and doubling time 5.3 months (3.3-15.3). Two experienced dose-limiting toxicity: grade 3 diarrhoea and grade 3 alanine transferase elevation, both at HCQ 600mg BD. Most common treatment-related adverse events (AEs) were hypertension (91% all grade/18% grade 3), QTc prolongation (55%/0%), diarrhoea (36%/9%), and nausea (36%/0%). There were no grade 4 AEs or deaths. While there were no PSA responses (≥50% fall from baseline), PSA PFS by PCWG3 criteria was 5.5 months (2.0-9.0), and PSA doubling time was prolonged at 4 and 12 weeks in 82% and 45% respectively. ADT-free and metastasis-free survival are 14.3 months (95% CI 4.9-23.8) and 15.9 months (95% CI unevaluable) respectively. PK data will be presented. Conclusions: HCQ/SI demonstrated acceptable safety with MTD 600mg BD and RP2D 400mg BD. There is early signal of activity and phase II enrolment is to begin. Clinical trial information: NCT03513211.
Pretherapeutic first-in-human targeting trial of anti-hK2 antibody h11B6: A potential molecular vector for alpha-particle radioimmunotherapy.
Authors: Morris Michael J. , O' Donoghue Joseph A. , Chetty Dushen , Max Steven , Wanik Danielle , Russell Mike , Nyima Tenzin , Avadhani Anjali Narayan , Divgi Chaitanya R , Pandit-Taskar Neeta
Published: March 2021

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Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has focused to date on targeting prostate specific membrane antigen, an approach associated with salivary gland toxicity and variable lesion expression. New targets are needed. Human kallikrein-2 (hK2) is overexpressed in most prostate cancer, with minimal normal tissue expression or serum secretion. Humanized monoclonal antibody (mAb) h11B6 exclusively targets hK2 in pre-clinical studies. This phase 0 study (NCT04116164) is a first-in-human trial of [111In]-DOTA-h11B6 to determine the hk2-targeting potential of h11B6. Objective: The purpose of this ongoing protocol is to characterize the biodistribution of [111In]-DOTA-h11B6 and determine a suitable mAb mass that targets mCRPC with minimal non-tumor targeting. Methods: Patients with progressive mCRPC were enrolled. A single slow bolus infusion of 2 mg [111In]-DOTA-h11B6 (nominally 185 MBq [111In]), was administered IV with or without 8 mg h11B6. Patients were observed for adverse events (AE) for at least 2 weeks. Serial gamma camera imaging including at least one SPECT/CT scan was performed up to 8 days post-administration. Serial blood samples were obtained over 2 weeks to determine serum radioactivity and h11B6 protein levels. Dosimetry for normal organs was estimated using OLINDA-EXM. Results: Results for the first 6 patients are summarized in Table. Treatment was tolerated in all patients with no AEs and no evidence of enhanced accumulation in any organ including salivary glands. Initial volume of distribution appeared confined to the vascular compartment. Slow clearance of radioactivity from the vascular compartment was observed with gradual targeting to skeletal and non-skeletal lesions in all patients. Conclusions: h11B6 is a novel mAb that targets hK2, localizes to bone and soft tissue metastases, has no significant normal tissue uptake, and spares salivary glands. An IND for a phase I therapeutic study using [225Ac] has been secured. Clinical trial information: NCT04116164. [Table: see text]
Temporal trends and predictors in diagnosing pathologic node-positive prostate cancer in clinically node-negative patients.
Authors: Hutten Ryan , Parsons Matthew , Weil Christopher , Tward Jonathan David , Lester-Coll Nataniel Hernan , Johnson Skyler B
Published: March 2021

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Background: The management of men with pathologically node positive (pN+) prostate cancer (PCa) is controversial. Here, we describe the temporal patterns and predictors of incidental pN+ PCa men with clinically node negative (cN0) PCa. Methods: We performed a retrospective analysis of men with nonmetastatic, cN0, PCa from the National Cancer Database from 2010 to 2017. Clinical factors included in analysis were pretreatment PSA, pre-surgical International Society of Urological Pathology (ISUP) grade group (GG), clinical T-stage, margin status, and number of nodes sampled. Patient demographic factors included in analysis were age, comorbidity index, race, insurance status, and treatment facility type. We performed univariable and multivariable logistic regression to evaluate temporal trends in the rates of cN0,pN+ prostate cancer diagnosed over time. Two-level hierarchical logistic regression was used to identify covariates associated with pN+ disease. Patients were clustered within treatment facilities to account for individual facility practice patterns. Results: We identified 304,234 men with cN0 PCa who underwent radical prostatectomy (RP) between 2010 and 2017. Within this group 10,919 (3.59%) were found to have pN+ disease. During this period, the annual rate of pN+ PCa increased from 2.02% (n=822) in 2010 to 5.12% (n=2,072) in 2017 (p<0.001). On multivariable logistic regression, ISUP GG was most strongly associated with detection of pN+ PCa. Compared to ISUP GG1, GG2 (OR 3.5, p <0.001), GG3 (OR 8.8, p <0.001), GG4 (OR 12.6, p <0.001) and GG 5 (OR 26.5, p <0.001 ) were all significantly associated with pN+ PCa. Over the study period, the rates of pN+ identification increased from 5.5% to 9.4% in men with GG4, and from 13.4% to 19.5% in men with GG5 (p <0.001). Between 2010 and 2017, the rates of RP in GG4 and GG5 similarly increased by 12% and 16%, respectively (p <0.001). Other significant covariates are depicted in Table. 22% of the total variance was explained by inter-facility variation. Conclusions: The proportion of men with cN0 found to have pN+ PCa is increasing over time, with pN+ incidentally found in nearly 1 in 10 men with GG4 and 1 in 5 men with GG5 PCa. GG4 and GG5 are the strongest independent predictors of pN+ disease, while controlling for clinical and demographic factors. As incidental pN+ results in upstaging, often requiring adjuvant treatment with radiation and systemic therapies, these data are useful for informing discussions prior to RP. [Table: see text]
Abiraterone acetate in patients with metastatic castration-resistant prostate cancer, chemo-naive, who received a prior diethylstilbestrol therapy.
Authors: Bastos Diogo Assed , Pioner Giovani Thomaz , Panhoca Renato , Perez Marjo Deninson Cardenuto , Damião Ronaldo , Werutsky Gustavo , Vacari Estela Vacari , Ferreira Amanda Yaeza , Fabricio Vanessa Carvalho , Gidekel Rosemarie
Published: March 2021

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Background: The use of diethylstilbestrol (DES) for the treatment of metastatic castration resistant prostate cancer (mCRPC) is very common in developing countries. Retrospective data suggests that abiraterone acetate (AA) is active in patients that progressed to DES. This phase II study evaluated the efficacy and safety of abiraterone acetate in chemotherapy-naïve patients with metastatic CRPC who have progressed to DES. Methods: Patients with DES−refractory metastatic CRPC with ongoing ADT, serum testosterone level < 50 ng/dL and ECOG of 0-2 were included. All patients received AA 1,000 mg with prednisone 5 mg once daily in a 28 days cycles. The primary endpoint was the time to PSA progression (PSAP) by PCWG2 and was previously reported. We present here secondary endpoints: overall survival, PSA response, maximum PSA change from baseline and safety. Results: A total of 46 patients were enrolled, median age was 69.8 years, 76% had gleason > = 7 at diagnosis, median time from metastatic disease to DES discontinuation was 25.9 months, and a median duration of prior DES of 7.2 months. AA treatment resulted in median time to PSA progression of 7.3 months. PSA response rate (³ 50%) was 47.5% (95% CI: 36,1% to 68,5%) at 12 weeks and 57.5% (95% CI: 27.0% to 59.1%) at any time. 93.4% received chemotherapy after progression to AA. The median overall survival was 29.6 months. Substantial declines in serum androgens from baseline to week 12 occurred and in this group a higher proportion of PSA responses occurred. The incidence of adverse events (AEs) related to AA was 74% and prednisone 59%. Hypertension (21.7%), fatigue (19.6%) and oedema peripheral (13.0%) were the most frequent AA related AEs. The most frequent prednisone related AEs were hyperglycaemia (15.2%) hypertension (10.9%). Serious AEs occurred in 23.9% of subjects and 3 subjects (6.5%) died of AEs not related to study drugs. Conclusions: AA is well tolerated and demonstrated activity in mCRPC patients previously treated with DES, therefore it should be considered an option in chemo-naïve patients. Serum androgens levels tend to decrease with AA treatment and are associated with PSA responses. Clinical trial information: NCT02217566.
Gut microbiota-associated compounds increase lethal prostate cancer risk.
Authors: Naelitz Bryan Douglas , Reichard Chad A. , Wang Zeneng , Jia Xun , Li Jianbo , Stampfer Meir J. , Klein Eric A. , Hazen Stanley L. , Sharifi Nima
Published: March 2021

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Background: Gut-microbiota-mediated metabolism of trimethylamine-associated nutrients and amino acids has been linked to altered cholesterol metabolism and endothelial inflammation. However, the association between these compounds and lethal prostate cancer (PCa) remains unknown. Methods: A nested case-control study was performed using samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate the association between baseline serum levels of target metabolites (choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide, phenylacetylglutamine, hippuric acid, and p-cresol sulfate) and lethal PCa risk. Lethal cases were randomly matched to controls at a 1:3 ratio on the basis of age, race, and enrollment date. Multivariable logistic regression, conditioned on case status and adjusted for PSA and BMI, was performed to assess the association between analyte quartile (Q) with lethal PCa. Trend of increasing odd ratios (OR) was evaluated using the Cochran-Armitage test. Results: 173 lethal PCa cases and 519 controls were analyzed. Relative to those in Q1, cases with baseline levels of choline and betaine above the median exhibited increased odds of developing lethal PCa after adjusting for BMI and PSA (Table). Lethal PCa risk increased across quartiles of choline in a dose-dependent fashion ( P-trend: 0.005), but not for betaine (P-trend: 0.08). Higher serum levels of other trimethylamine-associated compounds including γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide were not consistently associated with PCa mortality. Baseline serum levels of phenylacetylglutamine, a gut-microbiota metabolite of phenylalanine, were associated with incident lethal PCa, with risk increasing across quantiles (P-trend: 0.003). Elevations in hippuric acid and p-cresol sulfate levels were not consistently associated with greater lethal PCa risk. Conclusions: Serum levels choline, betaine, and phenylacetylglutamine are associated with PCa mortality, underscoring the potential role of gut-microbiota-mediated metabolism in the biology of lethal PCa. Clinical trial information: NCT00002540. [Table: see text]