bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of treatment (tx)-induced fatigue in breast cancer (BC) patients (pts) using machine learning on genome-wide association (GWAS) data in the prospective CANTO cohort.
Authors: Lee Sangkyu , Deasy Joseph O. , Oh Jung Hun , Di Meglio Antonio , Boyault Sandrine , Rousseau-Tsangaris Marina , Besse Celine , Thomas Emilie , Boland-Augé Anne , Cottu Paul H. , Tredan Olivier , Levy Christelle , Martin Anne-Laure , Everhard Sibille , Ganz Patricia A. , Partridge Ann H. , Michiels Stefan , Deleuze Jean-Francois , Andre Fabrice , Luis Ines Maria Vaz Duarte 
Published: March 2020

11515 Background: Many BC survivors report fatigue. The relevant genomic correlates of fatigue after BC are not well understood. We applied a previously validated machine learning methodology (Oh 2017) to GWAS data to identify biological correlates of fatigue induced after tx. Methods: We analyzed 3825 BC pts with GWAS data (Illumina InfiniumExome24 v 1.1) from the CANTO study (NCT01993498). The outcome of this study was post-tx fatigue 1 year after the end of primary chemotherapy/radiotherapy/surgery using the EORTC C30 fatigue subscale (overall fatigue) and the EORTC FA 12 fatigue domains (physical/emotional/cognitive). For each domain, we limited the study group to those with zero baseline fatigue and defined severe fatigue change as score increase above the third quartile. We tested univariate correlations between severe fatigue in each domain and 496539 SNPs as well as relevant clinical variables. The machine learning prediction model based on preconditioning random forest regression (PRFR) (Oh et al., 2017), was then built using the SNPs with ancestry adjusted univariate p-value < 0.001 and clinical variables with Bonferroni adjusted p-value < 0.05. The model was validated in a holdout subset of the cohort. Gene set enrichment analysis (GSEA) was performed using MetaCore to identify key biological correlates relevant to tx-induced fatigue. Results: Distinct results were found by fatigue domain (table). GSEA showed that the cognitive fatigue model SNPs included biomarkers for cognitive disorders (p = 1.6 x 10-12) and glutamatergic synaptic transmission (p = 1.6 x 10-8). Conclusions: A SNP based model had differential performance by fatigue domain, with a potential genetic role on risk and biology for tx induced cognitive fatigue. Further research to explore biomarkers of tx induced fatigue are needed. [Table: see text]
Acupuncture versus cognitive behavioral therapy for cognitive impairment in cancer survivors with insomnia: Implications for personalized medicine.
Authors: Mao Jun J. , Liou Kevin , Root James , Li Qing Susan , Bao Ting , Garland Sheila N. , Ahles Tim 
Published: March 2020

11522 Background: Cognitive impairment is a prevalent condition among cancer survivors that lacks effective treatment and can be maintained and exacerbated by poor sleep. This study explored whether treating insomnia with acupuncture or Cognitive Behavioral Therapy for Insomnia (CBT-I) improves subjective and objective cognitive functions in cancer survivors. Methods: We analyzed cognitive outcomes from a pragmatic randomized trial comparing acupuncture versus CBT-I for cancer survivors with insomnia. Analysis was limited to those reporting cognitive impairment at baseline. Acupuncture and CBT-I were delivered over 8 weeks. Perceived cognitive ability was assessed using the Brown Attention-Deficit Disorder Scale (BADDS). Objective cognitive function was evaluated with the Buschke Selective Reminding Test (BSRT). All outcomes were evaluated at baseline, Week 8 (end of intervention), and Week 20 (12 weeks post-intervention). Results: Among 99 cancer survivors, mean age was 60.4 years, 56.6% were women, and 26.3% were non-white. The most common cancer types were breast (31.3%) and prostate (19.2%). Perceived cognitive ability improved in both acupuncture and CBT-I groups at weeks 8 and 20 relative to baseline (all P < 0.001). No significant between-group differences were noted in BADDS total score (p = 0.28), but the CBT-I group demonstrated a better BADDS attention subscale score than the acupuncture group at weeks 8 and 20 (p = 0.031). With regards to objective cognitive functions assessed by BSRT, acupuncture improved attention (p = 0.017), learning (p = 0.040), and memory (p = 0.0020) at Week 8, whereas CBT-I only improved attention at Week 20 (p = 0.0002); between-group differences were not statistically significant. Conclusions: Among cancer survivors with insomnia, both acupuncture and CBT-I improved cognitive impairment relative to baseline, but their relative effects differed: the CBT-I group showed slightly better subjective attention, whereas the acupuncture group may have improved objective memory. Further investigation of these two therapies may lead to effective and personalized interventions for cancer survivors. Clinical trial information: NCT02356575.
Safety, tolerability, and PK of topical calcitriol formulation for treatment of chemotherapy-induced alopecia (CIA) in patients receiving taxane-based regimen: Final results.
Authors: Lacouture Mario E. , Sarangarajan Rangaprasad , Jimenez Joaquin Juan , Kiebish Michael A. , Narain Niven R. , Berman Brian , Goldfarb Shari Beth 
Published: March 2020

11608 Background: Chemotherapy-induced alopecia (CIA) following taxane-based treatment regimen is due to direct toxicity of these agents on rapidly dividing cells within hair follicles. Currently no oral or topical agents have been approved for prevention of CIA. In murine studies, topical calcitriol reduced CIA, likely due to arrest of cell cycle in healthy hair follicles, and reduction in the sensitivity of follicular epithelium to chemotherapy. Methods: A 3+3 dose-escalation strategy was used in this Phase 1 study with 3-6 patients at six dose levels (5/10/20/40/60/80 μg/mL) were assessed for safety and tolerability of BPM31543. Patients with a diagnosis of breast cancer, gynecologic cancer or sarcomas receiving a taxane-based chemotherapy regimen applied 1mL of the formulation to the scalp BID, ≥ 5 days prior to starting chemotherapy for at least 3 months or until treatment completed. Safety and efficacy assessments included AE monitoring, PK analysis, blinded photographic assessments and patient self-assessment. Results: 22/23 (95.7%) female patients receiving treatment and included in the safety population experienced at least one TEAE. The most frequently experienced TEAEs were alopecia (14 pts; 60.9%), fatigue (11 pts; 47.8%), nausea (9 pts; 39.1%), peripheral sensory neuropathy (7 pts; 30.4%), and maculopapular rash and vitamin D increased each in six patients (26.1%). Of these, elevated vitamin D and rash were possibly or probably related to treatment. Fatigue, nausea, and neuropathy were likely due to chemotherapy. In 18 patients included in the post-dose versus pre-treatment comparison, there was no dose-dependency on systemic levels of calcitriol. Hair loss < 50% from baseline was observed in 8 patients at week 7 that was maintained at week 15 in 2 patients. Conclusions: Study results showed BPM31543 applied topically twice daily to the scalp in patients receiving taxane-based chemotherapy was safe and well-tolerated. No DLT was observed up to 80 µg/mL dose and no MTD level was reached. There was a signal of potential efficacy detected at each dose level. A seamless Phase 2/3 trial strategy for clinical development is planned. Clinical trial information: NCT01588522.
Advanced cancer patients’ changes in terminal illness understanding (TIU) and their psychological well-being.
Authors: George Login S. , Shen Megan Johnson , Maciejewski Paul K. , Epstein Andrew S. , Prigerson Holly Gwen 
Published: March 2020

11617 Background: Although accurate TIU is necessary for informed treatment decision-making, clinicians worry that patients’ recognition of the terminal nature of their illness may lower psychological well-being. This study examines if such recognition is associated with lowered psychological well-being, that persists over time. Methods: Data came from 87 advanced cancer patients, with a life expectancy of less than 6 months. Patients were assessed pre and post an oncology visit to discuss cancer restaging scan results, and again one month later (follow-up). TIU was assessed at pre and post as the sum of four indicator variables — understanding of terminal nature of illness, curability, stage, and life-expectancy — and a TIU change score was computed (post minus pre). Psychological well-being (psychological symptoms subscale, McGill questionnaire) was assessed at pre, post, and follow-up, and two change scores were computed (post minus pre; follow-up minus post). Results: Changes toward more accurate TIU was associated with a corresponding decline in psychological well-being ( r = -0.33, p < .01), but thereafter was associated with subsequent improvements in psychological well-being ( r = .40, p < .001). This pattern persisted even after adjustment for relevant demographic factors, prognostic discussion, scan results, and physical well-being change. TIU change scores ranged from positive to negative, with some participants showing improvements in TIU ( n = 19), some showing decrements in TIU ( n = 14), and others showing stable TIU ( n = 54). Among patients with improved TIU, psychological well-being initially decreased, but subsequently recovered [7.03 (2.23) to 6.30 (1.80), to 7.63 (2.08)]; the stable TIU group showed relatively unchanged well-being [7.34 (2.37) to 7.45 (2.32), to 7.36 (2.66)], and the less accurate TIU group showed an initial improvement followed by a subsequent decline [6.30 (2.62) to 7.36 (2.04), to 5.63 (3.40)]. Conclusions: Improved TIU may be associated with initial decrements in psychological well-being, followed by patients rebounding to baseline levels. Concerns about psychological harm may not need to be a deterrent to having prognostic discussions with patients.
Efficacy of platinum-pemetrexed combination chemotherapy in ALK+ non-small cell lung cancer refractory to second-generation ALK TKIs.
Authors: Lin Jessica Jiyeong , Schoenfeld Adam Jacob , Zhu Viola Weijia , Yeap Beow Y. , Chin Emily , Rooney Marguerite , Plodkowski Andrew J. , Digumarthy Subba , Dagogo-Jack Ibiayi , Gainor Justin F. , Ou Sai-Hong Ignatius , Riely Gregory J. , Shaw Alice Tsang 
Published: March 2020

9067 Background: Second-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first- and second-line therapies in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). After progression on second-gen TKI(s), standard options include platinum (PT)-based chemotherapy (chemo) or the third-gen ALK TKI lorlatinib. The efficacy of PT-based chemo is established in treatment-naive pts but is undefined in pts who have failed prior ALK TKIs. Here we evaluate the efficacy of PT/pemetrexed (pem)-based chemo in pts with ALK+ NSCLC refractory to second-gen TKIs. Methods: A retrospective study was performed at three institutions. Pts were eligible if they had advanced ALK+ NSCLC refractory to ≥1 second-gen TKI, and received PT-pem-based chemo. Medical records and imaging were reviewed to determine outcomes. Results: Among 55 eligible pts, chemo regimens included: PT/pem (31/55, 56%), PT/pem/bevacizumab (bev) (6/55, 11%), PT/pem/PD-1 inhibitor (3/55, 5%), PT/pem with ALK TKI (8/55, 15%), PT/pem/bev with TKI (6/55, 11%), and PT/pem/PD-1 inhibitor with TKI (1/55, 2%). Pts had received one (6/55, 11%), two (38/55, 69%), or more (11/55, 20%) prior TKIs. Six pts (11%) previously received adjuvant or neoadjuvant chemo. Radiographic data for response evaluation was available for 39 pts. Among 36 pts with measurable baseline disease, confirmed ORR was 31% (11/36; 95% CI, 16-48%); 13 (36%) had stable disease. The median duration of response was 5.4 months (95% CI, 1.5-7.1 months). The median progression-free survival (PFS) for the entire cohort was 4.0 months (95% CI, 2.8-4.6 months). Chemo (PT/pem +/- bev or PD-1 inhibitor) plus ALK TKI (n = 15) was associated with a significant increase in PFS compared to chemo without TKI (n = 40) (median PFS 6.8 vs 3.2 months; HR 0.306; p = 0.002). Similarly, PT/pem plus ALK TKI (n = 8) was associated with increased PFS compared to PT/pem without TKI (n = 31) (median PFS 6.8 vs 2.9 months; HR 0.358; p = 0.036). Conclusions: The efficacy of PT-pem-based chemo is limited after failure of second-gen ALK TKIs but may be higher in pts who receive chemo plus ALK TKI, suggesting a potential role for ongoing ALK inhibition. The modest benefit of PT-pem-based chemo highlights the need for other therapeutic strategies for pts refractory to second-gen TKIs.
Substandard Cisplatin Found While Screening the Quality of Anticancer Drugs From Addis Ababa, Ethiopia
Authors: Eberle Madeline S. , Ashenef Ayenew , Gerba Heran , Loehrer Patrick J. , Lieberman Marya 
Published: March 2020

PURPOSE A postmarket evaluation of chemotherapy dosage forms in Ethiopia was conducted to test the accuracy of the chemoPAD, a paper analytical device for drug quality screening. MATERIALS AND METHODS In September of 2018 in Addis Ababa, Ethiopia, 41 anticancer drug dosage forms (representing 4 active ingredients, 5 brands, and 7 lot numbers) were collected and were rapidly screened for quality using a chemotherapy paper analytical device (chemoPAD). Confirmatory analysis via high performance liquid chromatography was conducted. RESULTS The chemoPAD showed that the correct active pharmaceutical ingredient was present in doxorubicin, methotrexate, and oxaliplatin injectable dosage forms. However, 11 of 20 cisplatin samples failed the screening test. Confirmatory assay by high-performance liquid chromatography showed that all 20 cisplatin samples—comprising three lot numbers of a product stated to be Cisteen—were substandard, containing on average 54% ± 6% of the stated cisplatin content. Inductively coupled plasma optical emission spectroscopy analysis of five representative samples found 57% to 71% of the platinum that should have been present. The sensitivity of the chemoPAD for detection of falsified products could not be measured (as none were present in these samples), but the selectivity was 100% (no false positives). The sensitivity for detection of substandard products was 55%, and the selectivity was 100% (no false positives). CONCLUSION Although instrumental analysis by pharmacopeia methods must remain the gold standard for assessing overall drug quality, these methods are time consuming and patients could be exposed to a bad-quality drug while clinical workers wait for testing to be performed. The chemoPAD technology could allow clinicians to check at the point of use for serious problems in the quality of chemotherapy drugs on a weekly or monthly schedule.
The FSH–HIF-1α–VEGF Pathway Is Critical for Ovulation and Oocyte Health but Not Necessary for Follicular Growth in Mice
Authors: Li Chengyu , Liu Zhaojun , Li Weijian , Zhang Liangliang , Zhou Jilong , Sun Minghong , Zhou Jiaqi , Yao Wang , Zhang Xuan , Wang Honghui , Tao Jingli , Shen Ming , Liu Honglin 
Published: March 2020

Abstract
Follicle-stimulating hormone (FSH)-induced growth of ovarian follicles is independent of follicular vascularization. Recent evidence has indicated that follicular vascularization is critical to ovarian follicle development and survival. FSH, a gonadotropin that induces follicular growth and development, also acts as the major survival factor for antral follicles. FSH has been reported to stimulate angiogenesis in the theca layers mediated in part by the vascular endothelial growth factor A (VEGFA) and the transcription factor hypoxia inducible factor 1α (HIF-1α). However, it remains largely undetermined whether FSH-dependent growth and survival of antral follicles relies on FSH-induced vascularization. Here, we first demonstrated that induction of angiogenesis through the FSH–HIF–1α-VEGFA axis is not required for FSH-stimulated follicular growth in mouse ovary. FSH increased the total number of blood vessels in mouse ovarian follicles, which was correlated with elevated expression of VEGFA and HIF-1α in granulosa cells. In contrast, blocking of follicular angiogenesis using inhibitors against the HIF-1α-VEGFA pathway repressed vasculature formation in follicles despite FSH administration. Interestingly, by measuring follicular size and ovarian weight, we found that the suppression of angiogenesis via HIF-1α–VEGFA pathway did not influence FSH-mediated follicular growth. However, inhibition of FSH-induced follicular vascularization by PX-478, a small-molecule inhibitor that suppresses HIF-1α activity, blocked ovulation and triggered atresia in large follicles. On the other hand, PX-478 injection reduced oocyte quality via impairing the meiotic apparatus, showing a prominently defective spindle assembly and actin dynamics. Collectively, our findings unveiled a vascularization-independent effect of FSH on follicular growth, whereas follicular survival, ovulation, and oocyte development relies on FSH-mediated angiogenesis in the follicles.
Quantifying differences in femoral head and neck asphericity in CAM type femoroacetabular impingement and hip dysplasia versus controls using radial 3DCT imaging and volumetric segmentation
Authors: Schauwecker Natalie , Xi Yin , Slepicka Chenelle , Dessouky Riham , Fey Nicholas , Chatzinoff Yonatan , Chopra Rajiv , Wells Joel , Chhabra Avneesh 
Published: March 2020

Objective:
Femoroacetabular impingement (FAI) and hip dysplasia are the most common causes of groin pain originating from the hip joint. To date, there is controversy over cut-off values for the evaluation of abnormal femoral head-neck anatomy with significant overlap between the normal and abnormal hips. Our aim was to perform three-dimensional CT analysis of femoral head and bump anatomy to quantify common hip pathologies (FAI and hip dysplasia) vs controls.

Methods:
Consecutive patients who underwent three-dimensional CT imaging for hip dysplasia or CAM type FAI were compared to asymptomatic controls. α angles on radial CT and 3D volumetric femoral head and bump segmentations were performed by two readers. Inter- and intrapatient comparisons were performed including interreader and receiver operating characteristic analyses.

Results:
25 FAI patients, 16 hip dysplasia patients and 38 controls were included. FAI and dysplasia patients exhibited higher α angles and higher bump-head volume ratios than the controls (p &lt; 0.05). Larger bump volumes were found among FAI than dysplasia patients and contralateral hips of FAI patients were also different than the controls. α angle at 2 o’clock and bump to head ratio showed the highest area under the curve for patients vs controls. The interreader reliability was better for volumetric segmentation (intraclass correlation coefficient = 0.35–0.84) as compared to the α angles (intraclass correlation coefficient = 0.11–0.44).

Conclusion:
Patients with FAI and dysplasia exhibit different femoral head anatomy than asymptomatic controls. Volumetric segmentation of femoral head and bump is more reliable and better demonstrates the bilateral femoral head anatomy differences in hip patients vs controls.

Advances in knowledge:
Utilizing information from 3D volumetric bump assessment in patients with FAI and dysplasia, the physicians may be able to more objectively and reliably evaluate the altered anatomy for better pre-surgical evaluation.
UK audit of target volume and organ at risk delineation and dose optimisation for cervix radiotherapy treatments
Authors: Cannon Jennifer , Bownes Peter , Mason Joshua , Cooper Rachel 
Published: March 2020

Objective:
Assessment of the extent of variation in delineations and dose optimisation performed at multiple UK centres as a result of interobserver variation and protocol differences.

Methods:
CT/MR images of 2 cervical cancer patients previously treated with external beam radiotherapy (EBRT) and Brachytherapy were distributed to 11 UK centres. Centres delineated structures and produced treatment plans following their local protocol. Organ at risk delineations were assessed dosimetrically through application of the original treatment plan and target volume delineations were assessed in terms of variation in absolute volume and length, width and height. Treatment plan variation was assessed across all centres and across centres that followed EMBRACE II. Treatment plans were assessed using total EQD2 delivered and were compared to EMBRACE II dose aims. Variation in combined intracavitary/interstitial brachytherapy treatments was also assessed.

Results:
Brachytherapy target volume delineations contained variation due to differences in protocol used, window/level technique and differences in interpretations of grey zones. Planning target volume delineations were varied due to protocol differences and extended parametrial tissue inclusion. All centres met EMBRACE II plan aims for PTV V95 and high-riskclinical target volume D90 EQD2, despite variation in prescription dose, fractionation and treatment technique.

Conclusion:
Brachytherapy target volume delineations are varied due to differences in contouring guidelines and protocols used. Planning target volume delineations are varied due to the uncertainties surrounding the extent of parametrial involvement. Dosimetric optimisation is sufficient across all centres to satisfy EMBRACE II planning aims despite significant variation in protocols used.

Advances in knowledge:
Previous multi-institutional audits of cervical cancer radiotherapy practices have been performed in Europe and the USA. This study is the first of its kind to be performed in the UK.
The validation of a commercial enzyme-linked immunosorbent assay and the effect of freeze-thaw cycles of serum on the stability of cortisol and testosterone concentrations in Aceh cattle
Authors: Gholib Gholib , Wahyuni Sri , Akmal Muslim , Hasan Muhammad , Agil Muhammad , Purwantara Bambang 
Published: March 2020

Background: To obtain accurate measurements of cortisol (C) and testosterone (T) in Aceh cattle, commercial enzyme-linked immunosorbent assay (ELISA) kits need to be carefully validated. Moreover, repeated freeze-thaw cycles during the storage of the samples may affect the stability of the hormones in the serum. Here, the reliability of C and T concentration measurements in the serum of Aceh cattle, was tested using commercial C and T ELISA kits designed to measure human C and T concentrations. Further, the effect of repeated freeze-thaw cycles on the stability of C and T concentrations in the serum was evaluated. Methods: Commercial C (Cat. no. EIA-1887) and T (Cat. no. EIA-1559) ELISA kits from DRG Instruments GmbH were validated through an analytical validation test (i.e., parallelism, accuracy, and precision) and a biological validation test (for C: effect of transportation on the C secretion; for T: the concentrations of T between bulls and cows). To test the effects of freeze-thaw cycles, cattle serum was subjected to the following treatments: (i) remained frozen at -20OC (control group); (ii) exposed to freeze-thaw cycles for two, four, six, and eight times (test groups). Results: Parallelism, accuracy, and precision tests showed that both C and T ELISA kits adequately measured C and T in the serum of Aceh cattle. Concentrations of C post-transportation were significantly higher than pre-transportation (p<0.01). Concentrations of T in bulls were significantly higher than in cows (p<0.01). After four to eight freeze-thaw cycles, C concentrations were significantly lower compared to the control group (all p < 0.05). In contrast, T concentrations remained stable (all p>0.05). Conclusions: Commercial C (EIA-1887) and T (EIA-1559) ELISA kits are reliable assays for measuring serum C and T, respectively, in Aceh cattle. Repeated freeze-thaw cycles significantly affected the stability of serum C, but did not for T.