bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of newborn’s body mass index using nationwide multicenter ultrasound data: a machine-learning study
Authors:   Korean Society of Ultrasound in Obstetrics and Gynecology Research Group, Lee Kwang-Sig , Kim Ho Yeon , Lee Se Jin , Kwon Sung Ok , Na Sunghun , Hwang Han Sung , Park Mi Hye , Ahn Ki Hoon
Published: March 2021

Background

This study introduced machine learning approaches to predict newborn’s body mass index (BMI) based on ultrasound measures and maternal/delivery information.

Methods

Data came from 3159 obstetric patients and their newborns enrolled in a multi-center retrospective study. Variable importance, the effect of a variable on model performance, was used for identifying major predictors of newborn’s BMI among ultrasound measures and maternal/delivery information. The ultrasound measures included biparietal diameter (BPD), abdominal circumference (AC) and estimated fetal weight (EFW) taken three times during the week 21 - week 35 of gestational age and once in the week 36 or later.

Results

Based on variable importance from the random forest, major predictors of newborn’s BMI were the first AC and EFW in the week 36 or later, gestational age at delivery, the first AC during the week 21 - the week 35, maternal BMI at delivery, maternal weight at delivery and the first BPD in the week 36 or later. For predicting newborn’s BMI, linear regression (2.0744) and the random forest (2.1610) were better than artificial neural networks with one, two and three hidden layers (150.7100, 154.7198 and 152.5843, respectively) in the mean squared error.

Conclusions

This is the first machine-learning study with 64 clinical and sonographic markers for the prediction of newborns’ BMI. The week 36 or later is the most effective period for taking the ultrasound measures and AC and EFW are the best predictors of newborn’s BMI alongside gestational age at delivery and maternal BMI at delivery.
Root canal curvature as a prognostic factor influencing the diagnostic accuracy of radiographic working length determination and postoperative canal axis modification: an in vitro comparative study
Authors: Faraj Bestoon Mohammed
Published: March 2021

Background

Radiographic analysis of tooth morphology is mandatory for accurate calibration of the degree of canal curvature angle and radiographic working length to its real dimensions in case difficulty assessment protocols. This study aimed to determine the impact of the degree of root canal curvature angle on maintaining the real working length and the original canal axis of prepared root canals using a reciprocating rotary instrumentation technique.

Methods

Radiographic image analysis was performed on 60 extracted single-rooted human premolar teeth with a moderate canal curvature (10°–25°) and severe canal curvature (26°–70°). Working length and longitudinal canal axis were determined using cone-beam computed tomography (CBCT) and digital periapical radiography. The real canal length was determined by subtracting 0.5 mm from the actual canal length. Root canals were prepared using the WaveOne Gold reciprocating file (Dentsply Maillefer, Ballaigues, Switzerland).

Results

There was no significant relation of the degree of canal curvature angle to the accuracy of radiographic working length estimated on CBCT and digital periapical radiographic techniques (P > 0.05). Postinstrumentation changes in the original canal axis between moderate and severe canal curvature angles, assessed on CBCT and periapical digital radiographic images were statistically non-significant (P > 0.05).

Conclusions

A standardized digital periapical radiographic method performed similarly to the CBCT technique near to its true working length. No significant interaction exists between the diagnostic working length estimation, postoperative root canal axis modification, and the degree of canal curvature angle, using reciprocating rotary instrumentation technique.
A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome
Authors: Chen Jing , Xia Zhongmin , Zhou Yulin , Ma Xiaomin , Wang Xudong , Guo Qiwei
Published: March 2021

Background

KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome.

Case presentation

A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident.

Conclusions

The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.
Label-free proteomics uncovers SMC1A expression is Down-regulated in AUB-E
Authors: Jia Yingxian , Luo Jie , Lan Yibing , Li Chunming , Ma Linjuan , Zhu Xiaoming , Ruan Fei , Zhou Jianhong
Published: March 2021

Background

While heavy menstrual bleeding (HMB) is a prevalent symptom among women with abnormal uterine bleeding caused by endometrial disorder (AUB-E) seeking gynecologic care, the primary endometrial disorder remains poorly understood.

Methods

Five human endometrial samples from women with AUB-E and the age-matched healthy women were selected, respectively. Proteins from the samples were analyzed by a linear ion trap (LTQ)-Orbitrap Elite mass spectrometer based label-free proteomic approach. The purpose protein was validated by western blot and immunohistochemistry staining.

Results

A total of 2353 protein groups were quantified under highly stringent criteria with a false discovery rate of < 1% for protein groups, and 291 differentially expressed proteins were significantly changed between the two groups. The results showed that the down-regulation of structural maintenance of chromosomes protein 1A (SMC1A) in AUB-E patients. Next, this change in the glandular epithelial cells was validated by immunohistochemistry.

Conclusion

The results indicated a novel mechanism for the cause of AUB-E, as down-expression SMC1A potentially regulated the cell cycle progression in endometrial glandular epithelium further led to bleeding.
Application of WALANT technique for repairing finger skin defect with a random skin flap
Authors: Xu Jianhua , Yin Lu , Cao Shuming , Zhan Haihua , Zhang Jianbing , Zhou Qiang , Gong Ketong
Published: March 2021

Background

Wide-awake local anesthesia no tourniquet (WALANT) technique has emerged among hand surgeons with other indications. Surgeries involving pedicled flap and revascularization are no longer used as contraindications. The present study aimed to evaluate the feasibility and merits of the WALANT technique in random skin flap surgery.

Methods

From May 2018 to March 2019, 12 patients with finger skin defects repaired with random skin flaps were reviewed. Abdominal skin flaps or thoracic skin flaps were used to cover the wound. Both the fingers and the donor sites were anesthetized by the WALANT technique. A 40-mL conventional volume consisted of a mixture of epinephrine and lidocaine. A volume of 5 mL was injected at the distal palmar for nerve block, the other 5 mL was injected around the wound for hemostasis, and the remaining was injected at the donor site of flaps for both analgesia and hemostasis. Baseline data with respect to sex, age, side, type of finger, donor sites, flap size, dosage of anesthetics, usage of finger tourniquet, intraoperative and postoperative pain, hemostasis effect, operation time, Disabilities of the Arm, Shoulder, and Hand Questionnaire (QuickDASH) score, and hospitalization expense, were collected.

Results

All patients tolerated the procedure, and none of them needed sedation. Single finger skin defect in 8 patients and double finger skin defect occurred in 4 patients; 5 patients were repaired by abdominal skin flaps, and 7 patients were repaired by thoracic skin flaps. The good surgical field visibility was 91.7%. All flaps survived adequately, without necrosis, pulling fingers out, and other complications. The average visual analog scale (VAS) score of the maximal pain was 1.1 in fingers vs. 2.1 in donor sites during the operation. On postoperative day one, the average VAS score of the maximal pain in fingers and donor sites was 1.3 and 1.1, respectively. The average hospitalization expense before reimbursement of the whole treatment was 11% less expensive compared to the traditional method. The average QuickDASH score was 9.1.

Conclusions

Under wide-awake anesthesia, patients have the ability to control their injured upper extremities consciously, avoiding the complications due to pulling flap pedicles. With the merits of safety, painlessness, less bleeding, and effectivity, the WALANT technique in random skin flaps is feasible and a reliable alternative to deal with finger skin defect.
Global mental health should engage with the ethics of involuntary admission
Authors: Wickremsinhe Marisha N.
Published: March 2021

Global mental health, as a field, has focused on both increasing access to mental health services and promoting human rights. Amidst many successes in engaging with and addressing various human rights violations affecting individuals living with psychosocial disabilities, one human rights challenge remains under-discussed: involuntary inpatient admission for psychiatric care. Global mental health ought to engage proactively with the debate on the ethics of involuntary admission and work to develop a clear position, for three reasons. Firstly, the field promotes models of mental healthcare that are likely to include involuntary admission. Secondly, the field aligns much of its human rights framework with the UN Convention on the Rights of Persons with Disabilities, which opposes the discriminatory use of involuntary admission on the basis of psychosocial disability or impairment. Finally, global mental health, as a field, is uniquely positioned to offer novel contributions to this long-standing debate in clinical ethics by collecting data and conducting analyses across settings. Global mental health should take up involuntary admission as a priority area of engagement, applying its own orientation toward research and advocacy in order to explore the dimensions of when, if ever, involuntary admission may be permissible. Such work stands to offer meaningful contributions to the challenge of involuntary admission.
AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain
Authors: Zeng Fei , Zhang Qiaosheng , Liu Yaling , Sun Guanghao , Li Anna , Talay Robert S. , Wang Jing
Published: March 2021

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.
High oil accumulation in tuber of yellow nutsedge compared to purple nutsedge is associated with more abundant expression of genes involved in fatty acid synthesis and triacylglycerol storage
Authors: Ji Hongying , Liu Dantong , Yang Zhenle
Published: March 2021

Background

Yellow nutsedge is a unique plant species that can accumulate up to 35% oil of tuber dry weight, perhaps the highest level observed in the tuber tissues of plant kingdom. To gain insight into the molecular mechanism that leads to high oil accumulation in yellow nutsedge, gene expression profiles of oil production pathways involved carbon metabolism, fatty acid synthesis, triacylglycerol synthesis, and triacylglycerol storage during tuber development were compared with purple nutsedge, the closest relative of yellow nutsedge that is poor in oil accumulation.

Results

Compared with purple nutsedge, high oil accumulation in yellow nutsedge was associated with significant up-regulation of specific key enzymes of plastidial RubisCO bypass as well as malate and pyruvate metabolism, almost all fatty acid synthesis enzymes, and seed-like oil-body proteins. However, overall transcripts for carbon metabolism toward carbon precursor for fatty acid synthesis were comparable and for triacylglycerol synthesis were similar in both species. Two seed-like master transcription factors ABI3 and WRI1 were found to display similar transcript patterns but were expressed at 6.5- and 14.3-fold higher levels in yellow nutsedge than in purple nutsedge, respectively. A weighted gene co-expression network analysis revealed thatABI3was in strong transcriptional coordination withWRI1and other key oil-related genes.

Conclusions

These results implied that pyruvate availability and fatty acid synthesis in plastid, along with triacylglycerol storage in oil bodies, rather than triacylglycerol synthesis in endoplasmic reticulum, are the major factors responsible for high oil production in tuber of yellow nutsedge, and ABI3 most likely plays a critical role in regulating oil accumulation. This study is of significance with regard to understanding the molecular mechanism controlling carbon partitioning toward oil production in oil-rich tuber and provides a valuable reference for enhancing oil accumulation in non-seed tissues of crops through genetic breeding or metabolic engineering.
Deletion at an 1q24 locus reveals a critical role of long noncoding RNA DNM3OS in skeletal development
Authors: Yu Ting-ting , Xu Qiu-fan , Li Si-Yang , Huang Hui-jie , Dugan Sarah , Shao Lei , Roggenbuck Jennifer A. , Liu Xiao-tong , Liu Huai-ze , Hirsch Betsy A. , Yue Shen , Liu Chen , Cheng Steven Y.
Published: March 2021

Background

Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology.

Results

Here we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690 kb deletion at Chr.1q24.2 encompassing a noncoding RNA gene, DNM3OS, embedded on the opposite strand in an intron of the DYNAMIN 3 (DNM3) gene. We show that lncRNA DNM3OS sustains the proliferation of chondrocytes independent of two co-cistronic microRNAs miR-199a and miR-214. We further show that nerve growth factor (NGF), a known factor of chondrocyte growth, is a key target of DNM3OS-mediated control of chondrocyte proliferation.

Conclusions

This work demonstrates that DNM3OS is essential for preventing premature differentiation of chondrocytes required for bone growth through endochondral ossification.
Patient safety and public health concerns: poor dissolution rate of pioglitazone tablets obtained from China, Myanmar and internet sites
Authors: Rahman Mohammad Sofiqur , Yoshida Naoko , Tsuboi Hirohito , Maeda Erina , Ibarra Andrea Vanessa Velasco , Zin Theingi , Akimoto Yoshio , Tanimoto Tsuyoshi , Kimura Kazuko
Published: March 2021

Background

Poor quality medicines have serious implications for public health. The aim of this study was to explore the quality of the antidiabetic pioglitazone, using samples collected in China and Myanmar, and samples purchased online.

Methods

In this cross-sectional study, we examined samples (n = 163) collected from hospitals in Shanghai, China in 2012 (n = 44), products purchased via the internet and imported into Japan in 2013 (n = 59), and samples purchased in shops in Yangon, Myanmar in 2015 (n = 60). Collected samples were subjected to visual inspection, authenticity investigation and quality testing (potency, content uniformity and dissolution test) by high-performance liquid chromatography. Samples were rated as compliant or non-compliant based on the relevant pharmacopoeial acceptance criteria.

Results

Visual inspection of all samples revealed compliant products. However, responses from manufacturers during authenticity investigation were poor. Among the n = 44 samples from China, one was non-compliant in the potency test. Among the n = 59 samples personally imported into Japan, 38% of generic samples were found to be non-compliant. In Myanmar, 13.3% of samples were non-compliant. Non-compliant samples predominantly failed in the dissolution test. All non-compliant samples were generic.

Conclusions

Despite the apparent satisfactory outcome on the samples from China, pioglitazone samples collected in Myanmar and purchased online for personal import into Japan included many substandard products, which failed quality assessment predominantly because of poor dissolution. Internet providers did not comply with Japanese regulations in various respects.
Elevational distribution ranges of vascular plant species in the Baekdudaegan mountain range, South Korea
Authors: Shin Sookyung , Kim Jung-Hyun , Dang Ji-Hee , Seo In-Soon , Lee Byoung Yoon
Published: March 2021

The climate is changing rapidly, and this may pose a major threat to global biodiversity. One of the most distinctive consequences of climate change is the poleward and/or upward shift of species distribution ranges associated with increasing temperatures, resulting in a change of species composition and community structure in the forest ecosystems. The Baekdudaegan mountain range connects most forests from the lowland to the subalpine zone in South Korea and is therefore recognized as one of the most important biodiversity hotspots. This study was conducted to understand the distribution range of vascular plants along elevational gradients through field surveys in the six national parks of the Baekdudaegan mountain range. We identified the upper and lower distribution limits of a total of 873 taxa of vascular plants with 117 families, 418 genera, 793 species, 14 subspecies, 62 varieties, two forms, and two hybrids. A total of 12 conifers were recorded along the elevational gradient. The distribution ranges of Abies koreana, Picea jezoensis, Pinus pumila, and Thuja koraiensis were limited to over 1000 m above sea level. We also identified 21 broad-leaved trees in the subalpine zone. A total of 45 Korean endemic plant species were observed, and of these, 15 taxa (including Aconitum chiisanense and Hanabusaya asiatica) showed a narrow distribution range in the subalpine zone. Our study provides valuable information on the current elevational distribution ranges of vascular plants in the six national parks of South Korea, which could serve as a baseline for vertical shifts under future climate change.
The COVID-19 pandemic should be last orders for poor care of people with neurodevelopmental disorders
Authors: Strydom Andre , Corcoran Elizabeth , Rebillat Anne-Sophie
Published: March 2021

We explore whether the needs of individuals with neurodevelopment disorders have been overlooked during the coronavirus disease 2019 (COVID-19) pandemic and set out the issues that need to be considered in response to future health crises and pandemics.
Preliminary results from a phase II trial of docetaxel before castration with degarelix in men with newly diagnosed metastatic prostate cancer.
Authors: Gourdin Theodore Stewart , Lilly Michael B. , Hussain Arif , Savage Stephen , Clarke Harry S , Sion Amy Marie , Grubb Robert , Sellman David , Dincman Toros , Mikoll Jennifer , Patel Pooja , Marshall David T. , Li Hong , Keane Thomas E.
Published: March 2021

116

Background: Randomized trials have demonstrated a survival advantage to administering docetaxel (D) shortly after initiation of androgen deprivation therapy (ADT) in men with newly diagnosed hormone sensitive metastatic prostate cancer (hsMPC). Clinical trials in breast cancer, research in prostate cancer cell lines, and pharmacokinetic analyses of D clearance in the castrate state, suggest increased efficacy of chemotherapy administered separately from hormone suppression. We proposed that treatment with D before ADT might improve outcomes in newly diagnosed hsMPC. Methods: In an ongoing phase II study (NCT03069937), men with newly diagnosed hsMPC were treated with 4 cycles of D (75mg/m2) every 21 days without ADT followed by 2 cycles of D concurrent with the LHRH antagonist degarelix (Deg) administered every 4 weeks. The Deg alone was continued for a total of 7 injections. Men were trial eligible with high or low volume disease by CHAARTED criteria. Bicalutamide was allowed for < 30 days before trial entry, but LHRH directed therapy was not permitted. The primary endpoint for this trial is percentage of men obtaining PSA < 0.2 ng/ml. Pre-specified secondary endpoints examined here after 4 cycles of docetaxel alone are safety, and efficacy defined by PSA (decrease by > 50%) and radiographic responses. Results: At time of this abstract, 50 patients have been enrolled to trial. Two patients withdrew after 1 cycle of D, and 4 patients have not yet completed 4 cycles. Of the 50 patients evaluable for safety, 6 (12%) had Grade 3 toxicities related to D. No Grade 4/5 toxicities were reported. Of patients who completed 4 cycles of D, 24/44 (55%) had a PSA response and 34/44 (77%) had PSA decline from baseline. All but two patients with declining PSA had stable or improved radiographic imaging. Six of the 44 patients (14%) had PSA progression (>25% increase) with D therapy, 3 of whom also had radiographic progression. Every patient with PSA response after 4 cycles D had PSA decline after 2 cycles. No patient with PSA decline after 2 cycles had PSA progression after 4 cycles. PSA response rate was stratified by baseline variables in table below. Conclusions: In hsMPC patients, 4 cycles D without ADT appears to be a safe and active therapy. Treatment with bicalutamide prior to the start of D predicts poorer PSA response. This result strengthens our hypothesis that sensitivity of hsMPC to taxane therapy may be enhanced if ADT is postponed. Baseline genomics will be analyzed, and we hope to correlate responses to D alone with later primary efficacy outcomes. Clinical trial information: NCT03069937. [Table: see text]
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Final efficacy and safety results.
Authors: Kessel Adam , McFarland Taylor Ryan , Sayegh Nicolas , Morton Kathryn , Sirohi Deepika , Kohli Manish , Swami Umang , Nussenzveig Roberto , Agarwal Neeraj , Maughan Benjamin Louis
Published: March 2021

135

Background: We previously reported that treatment with EZ+RA was associated with a decline in serum bone metabolism markers (BMM), which correlated with improved outcomes compared to EZ alone (Agarwal N et al, Clinical Cancer Research, 2020, PMID 31937614). Here we report the final efficacy and safety results for this trial. Methods: In this phase 2 trial (NCT02199197), patients (pts) with progressive mCRPC were treated with EZ (160 mg daily) ±RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives of change in bone markers and safety have been reported previously. Secondary objectives included comparison of PSA progression free survival (PFS), overall survival (OS), and long term safety in all pts receiving RA+EZ vs EZ alone. Post hoc analysis included comparison of PSA-PFS2 (defined as time from start of protocol therapy to PSA progression on subsequent therapy or death whichever occurred earlier), time to subsequent/next therapy (TTNT), and long term safety. Survival analysis and log-rank tests was performed using the R statistical package v.4.0.2 ( https://www.r-project.org ). Statistical significance was defined as P<0.05. Results: Between 08/2014 and 11/2017, 47 pts were eligible and enrolled. Median follow up was 22 months (range 3.2-71.5). Thirty-five pts received RA+EZ and 12 pts received EZ alone. Receipt of prior abiraterone was allowed and was balanced between two groups: 60% in RA+EZ vs. 64% in EZ pts. Final efficacy results: TTNT, PSA-PFS2 were significantly improved in the RA+EZ pts over EZ alone pts, and all other efficacy parameters were numerically improved in RA+EZ pts (Table). Final safety results: none of the 12 EZ alone pts had any fracture; two of 35 RA+EZ pts were found to have incidental grade 1 asymptomatic fracture at the site of bone metastasis on routine imaging, at 15 and 31 months respectively after the last dose of RA, and did not require any intervention. No patients developed bone marrow disorders during the follow-up period. Efficacy and safety data will be elaborated during the meeting. Conclusions: In our study, EZ+RA resulted in significant long-term clinical benefit over EZ alone in pts with mCRPC without compromising safety. * NA&BLM; equal contribution. Clinical trial information: NCT02199197. [Table: see text]
Associations of circulating cell-free DNA (cfDNA) and clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Shevrin Daniel H. , Yang Mathew , Imas Polina , Gulukota Kamalakar ,   Northshore University Healthsystem
Published: March 2021

137

Background: Genomic profiling of patients (pts) with mCRPC is becoming more widely utilized to assist in prognosis and treatment. Liquid biopsies offer a non-invasive method of assessing gene alterations but questions remain regarding their validity, as well as the association of these alterations with relevant clinical outcomes. Methods: We present a retrospective analysis of 82 pts who underwent genomic profiling at the onset of mCRPC using the Guardant360 cfDNA assay. Clinical outcomes data was recorded in a structured note in the electronic medical record that allowed discrete data elements to be stored and analyzed. Patients received standard treatment with Abiraterone (Abi) and Enzalutamide (Enza) as well as chemotherapy. Relevant clinical outcome endpoints included overall survival (OS) and time on treatment with Abi and Enza (TT). These endpoints were compared between patients grouped by their gene alterations and treatment. Univariate and multivariate association analyses were performed. Results: The structured note was found to be valuable in capturing relevant discrete clinical outcomes data for detailed analysis. Median OS for the 82 pts was 58 months. 15 pts had insufficient cfDNA to perform the assay and these pts had a significantly longer OS than the 67 pts with sufficient cfDNA (median not reached vs 36 months, p = 0.004). The most commonly altered genes were AR and TP53 with 45% pts having alterations in both genes. Our analysis showed significantly shorter OS with BRAF (24 months, p = 0.008) and NF1 (20 months, p = 0.036) alterations. However, the significance was lost after multiple hypothesis correction. We observed that pts with co-occurrence of AR and BRAF had a significantly shorter OS (18.7 months, p = 0.031). BRCA2 mutations were observed in 9 pts and were associated with a significantly shorter TT (23 vs 38 months, p = 0.022) but lost significance after multiple hypothesis correction. Patients who received Abi followed by Enza had a significantly longer TT compared to pts who received the reverse sequence (38 months vs 23 months, p = 0.02). Conclusions: In this retrospective analysis, we did not identify any significant associations between specific gene alterations and relevant clinical outcomes. We observed a trend of shorter OS with BRAF and NF1 alterations and a shortened OS with co-occurrence of AR and BRAF alterations. These associations will require validation in a larger study. The presence of sufficient DNA to perform the assay was associated with shorter OS. The treatment sequence of Abi followed by Enza showed longer TT than the reverse sequence. The structured note allowed capture of relevant clinical outcomes data and is currently being utilized in a larger prospective genomic study of mCRPC.
Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Freeman Meredith MI , Jaeger Ellen , Zhu Jason , Phone Audrey , Nussenzveig Roberto , Caputo Sydney , Ravindranathan Deepak , Layton Jodi Lyn , Nandagopal Lakshminarayanan , Kessel Adam , Desai Arpita , Koshkin Vadim S , Basu Arnab , Bilen Mehmet Asim , Swami Umang , Garcia Jorge A. , Agarwal Neeraj , Burgess Earle F , Sartor A. Oliver , Barata Pedro C.
Published: March 2021

17

Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.
Association of reductions in PSA screening across states with increased metastatic prostate cancer in the United States.
Authors: Sharma Vidit , Venkataramana Abhishek , Comulada W. Scott , Litwin Mark S. , Saigal Christopher
Published: March 2021

228

Background: While PSA screening was found to reduce prostate cancer metastasis and mortality in a large European randomized trial, PSA screening has also resulted in over-treatment of prostate cancer with significant quality-of-life implications. As a result, the US Preventive Services Task Force (USPSTF) did not recommend PSA screening in 2008 and 2012. It is unknown if reductions in PSA screening were responsible for increased metastatic prostate cancer in the United States. We test this hypothesis by associating longitudinal variations across individual states in PSA screening with their incidence of metastatic prostate cancer at diagnosis from 2002 to 2016. Methods: Age-adjusted incidences of metastatic prostate cancer at diagnosis per 100,000 men were obtained from the North American Association of Central Cancer Registries in 2002 – 2016 for each state. Survey-weighted PSA screening estimates for each state were extracted from the Behavioral Risk Factor Surveillance System, which collects this information for men at least 40 years of age every 2 years from 2002 onward. PSA screening and metastasis data were collated as a multi-panel time series and then analyzed using a random-effects linear regression model with random effects at the state level. Results: There was significant variation between states in the percent of men age >40 years who reported ever receiving PSA screening (range 40.1% to 70.3%) and in the age-adjusted incidence of metastatic prostate cancer at diagnosis (range 3.3 to 14.3 per 100,000). From 2008 to 2016, the mean percentage of men screened decreased (61.8% to 50.5%) whereas the mean incidence of metastatic prostate cancer at diagnosis increased (6.4 to 9.0 per 100,000; Bonferroni adjusted p < 0.001 for both). A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were associated with increased metastatic prostate cancer (regression coefficient per 100,000 men: 14.9, 95% CI 12.3 – 17.5, p < 0.001). This indicated that states with larger declines in PSA screening had larger increases in the incidence of metastatic prostate cancer at diagnosis. Variation in PSA screening explained 27% of the longitudinal variation in metastatic prostate cancer within states. Conclusions: In the context of randomized trial data demonstrating a metastasis reduction with PSA screening, our study strengthens the epidemiologic evidence that reductions in PSA screening may explain some of the recent increase in metastatic prostate cancer at diagnosis in the United States. The trend of rising metastatic disease at diagnosis is a worrisome consequence that needs attention. Thus, we support shared-decision making policies, such as the 2018 USPSTF update, that may optimize PSA screening utilization to reduce the incidence of metastatic prostate cancer in the United States.
Concordance of BRCA1, BRCA2 (BRCA), and ATM mutations identified in matched tumor tissue and circulating tumor DNA (ctDNA) in men with metastatic castration-resistant prostate cancer (mCRPC) screened in the PROfound study.
Authors: Chi Kim N. , Barnicle Alan , Sibilla Caroline , Lai Zhongwu , Corcoran Claire , Williams J. Andrew , Barrett J Carl , Adelman Carrie A. , Qiu Ping , Easter Ashley , Dearden Simon , Harrington Elizabeth
Published: March 2021

26

Background: Not all mCRPC patients have available or sufficient tissue for multigene molecular testing. In the Phase 3 PROfound study, olaparib significantly improved radiographic progression-free survival compared with physician’s choice of abiraterone or enzalutamide in men with homologous recombination repair (HRR)-gene-mutated mCRPC (de Bono et al. N Engl J Med 2020). Overall, 31% of patients’ tissue samples failed molecular screening during the study, showing the need for additional testing methods to detect patients with HRR-gene-mutated cancers. We evaluated the utility of plasma-derived ctDNA to identify deleterious BRCA and ATM mutations in screened patients from PROfound. Methods: Tumour samples were prospectively tested at Foundation Medicine, Inc (FMI) using an investigational next-generation sequencing test (based on FoundationOne CDx) to inform trial eligibility. Matched ctDNA samples were sequenced at FMI with the FoundationOne Liquid CDx assay. Tissue samples were clinically heterogeneous regarding location and timing of collection; plasma samples were collected as part of screening in PROfound. Results: 81% (503/619) of ctDNA samples tested yielded a result, of which 491 had a tumour result. BRCA and ATM status in tissue compared with ctDNA reported 81% (95% CI 75–87%) positive percentage agreement (PPA) and 92% (95% CI 89–95%) negative percentage agreement (NPA), with tissue as reference (Table). Further concordance and discordance measures will be presented. Conclusions: High concordance between tumour tissue and ctDNA supports the development of ctDNA testing as a minimally invasive method to identify patients with HRR-gene-mutated mCRPC and guide treatment decisions, particularly for those with insufficient tissue for genomic analyses. Clinical trial information: NCT02987543. [Table: see text]
Outcomes of first-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Gan Chun Loo , Dudani Shaan , Wells J Connor , Schmidt Andrew Lachlan , Bakouny Ziad , Szabados Bernadett , Parnis Francis , Wong Shirley , Lee Jae-Lyun , de Velasco Guillermo , Pal Sumanta K. , Davis Ian D. , Kanesvaran Ravindran , Wood Lori , Kollmannsberger Christian K. , McKay Rana R. , Beuselinck Benoit , Donskov Frede , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2021

276

Background: Ipilimumab and nivolumab (IPI-NIVO) and IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE) are now standard of care 1L treatment options for mRCC. However, there is limited head-to-head comparative evidence between these strategies. Methods: Using the IMDC dataset, patients treated with a 1L IOVE combination (pembrolizumab axitinib, avelumab axitinib and nivolumab cabozantinib) were compared with those treated with IPI-NIVO. The outcomes of interest were overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). A preplanned subgroup analysis of the IMDC intermediate/poor risk population was conducted. Hazard ratios were adjusted for IMDC risk factors. Results: 723 patients were included for analysis (N=571 for IPI-NIVO and N=152 for IOVE). The median age was 60 in both groups. The proportion of patients with IMDC favorable, intermediate and poor risk disease in IPI-NIVO vs. IOVE groups were 9% vs. 33%, 58% vs. 53%, 33% vs. 14%, respectively. In the intermediate/poor risk groups (Table), ORR and median TD were lower and shorter in IPI-NIVO vs IOVE while no difference in median TTNT and OS was detected. The HR for death adjusting for IMDC criteria for IPI-NIVO vs. IOVE was 0.92 (95% CI 0.61-1.40, p=0.71). IMDC risk groups and the presence or absence of sarcomatoid histology, brain, liver or bone metastases were not associated with differences in OS between these treatments (all p>0.2). Patients that had dose delays or steroid use (defined as >40mg of prednisone equivalent/day) for immune related adverse events (irAEs) were associated with longer median TTNT (21.6 vs. 9.5 mons, p=0.02) and OS (NR vs. 44.4 mons, p=0.01) despite similar treatment durations (7.6 vs. 8.9 mons, p=0.77) compared to those without dose delays or steroid use. Conclusions: We were unable to detect any differences in OS between IPI-NIVO and IOVE regimens in the IMDC intermediate/poor risk groups and amongst various subgroups. Patients who experienced irAEs requiring dose delay or steroids had longer overall survival. [Table: see text]
Treatment sequence after first-line nivolumab plus ipilimumab or sunitinib monotherapy in patients with metastatic renal cell carcinoma (mRCC) using real-world data.
Authors: Geynisman Daniel M. , Faccone Jillian , Zhang Ying , Ejzykowicz Flavia , Stwalley Brian , Hamilton Melissa , Le Trong Kim , Huo Stephen
Published: March 2021

288

Background: The introduction of second-line (2L) nivolumab (NIVO) in 2015 (CheckMate 025) and first-line (1L) NIVO plus ipilimumab (NIVO+IPI) in 2018 (CheckMate 214) revolutionized the management of mRCC in the US. This study sought to leverage real-world (RW) data by applying CheckMate 214 inclusion criteria to develop a RW comparator for the trial to assess treatment patterns and sequences in RW patients (pts) with mRCC after receiving 1L NIVO+IPI or sunitinib (SUN). Methods: This retrospective study identified pts with clear cell mRCC from the Flatiron Health EHR-derived de-identified database who received 1L NIVO+IPI or SUN monotherapy on or after December 2015. Pts must have met the strict selection criteria from CheckMate 214 for this analysis. Evaluation of 1L, 2L, and third-line (3L) therapies was stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk (favorable [FAV] and intermediate/poor [I/P]). Results: Of 401 mRCC pts included in the study, 197 (49.1%) received NIVO+IPI and 204 (50.9%) received SUN as 1L therapy (Table). The median follow-up time was 10.1 months in NIVO+IPI pts and 20.2 months in SUN pts ( P < 0.0001). Among 66 (33.5%) NIVO+IPI pts who received 2L line therapy, the 2 most common therapies were cabozantinib (CABO; 50.0%), and pazopanib (PAZO; 12.1%). Among 119 (58.3%) SUN pts who received 2L therapy, the most common therapies were NIVO (48.7%), and PAZO (8.4%). The 2 most common 3L therapies were axitinib (AXI; 18.2%) or everolimus plus lenvatinib (EVE+LEN; 18.2%) for NIVO+IPI pts, and CABO (26.7%) or NIVO (15.0%) for SUN pts. The treatment sequence is similar between patients with FAV and I/P risk. Conclusions: In the RW setting, the treatment sequences after NIVO+IPI and SUN were largely similar across the IMDC risk groups. CABO was the most common therapy in 2L after NIVO+IPI in RW pts, and NIVO was the most common 2L therapy after SUN monotherapy, which was consistent with the sequence in the trial. [Table: see text]
Efficacy and safety of avelumab plus axitinib (A + Ax) versus sunitinib (S) in elderly patients with advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Motzer Robert J. , Choueiri Toni K. , Rini Brian I. , Miyake Hideaki , Uemura Hirotsugu , Albiges Laurence , Fujii Yosuke , Umeyama Yoshiko , Wang Jing , Mariani Mariangela , Schmidinger Manuela
Published: March 2021

301

Background: In the phase III JAVELIN Renal 101 trial (NCT02684006), A + Ax demonstrated significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) vs S in patients with previously untreated aRCC. The role of immune checkpoint + VEGFR inhibition in elderly patients remains unclear. Here we report the efficacy of A + Ax vs S by age group from the second interim analysis (IA) of overall survival (OS) and the safety of A + Ax by age group from the first IA. Methods: Patients were randomized 1:1 to receive A 10 mg/kg intravenously every 2 wk + Ax 5 mg orally twice daily or S 50 mg orally once daily for 4 wk (6-wk cycle). PFS and ORR per independent central review (RECIST 1.1), OS, and safety by age group (<65, ≥65 to <75, and ≥75 y) were assessed. Results: A total of 271/138/33 and 275/128/41 patients in each age group (<65, ≥65 to <75, and ≥75 y, respectively) were randomized to the A + Ax or S arm, respectively. The proportion of IMDC risk groups was generally well balanced between the A + Ax and S arm in each age group, although in the ≥75 y age group, the frequency of patients with intermediate risk was slightly higher in the A + Ax arm, and that of patients with favorable risk was slightly higher in the S arm. The percentages of patients with favorable/intermediate/poor risk in each age group were 19%/61%/19%, 28%/58%/13%, and 12%/76%/12% in the A + Ax arm vs 20%/63%/16%, 23%/60%/16%, and 24%/61%/15% in the S arm. At data cut-off (Jan 2019) for the second IA, median follow-up for OS and PFS was 19.3 vs 19.2 mo and 16.8 vs 15.2 mo for the A + Ax vs S arm, respectively. The table shows OS, PFS, and ORR by age group. In the A + Ax arm, the most common treatment-emergent adverse events (AEs) were diarrhea (62%/68%/42%), hypertension (49%/49%/55%), palmar-plantar erythrodysesthesia syndrome (37%/31%/15%), fatigue (37%/53%/30%), and nausea (34%/37%/21%) in each age group. Grade ≥3 treatment-emergent AEs and immune-related AEs were observed in 69%/74%/73% and 39%/40%/24% of patients in each age group, respectively. Conclusions: A + Ax demonstrated favorable efficacy across age groups, including patients aged ≥75 y. OS was still immature; follow-up for the final analysis is ongoing. The safety profile was generally consistent between age groups. Clinical trial information: NCT02684006 . [Table: see text]