julilili42/papers huggingface dataset:
Multicenter real-world data of adjuvant treatment and disease outcome of patients with melanoma with high-risk of recurrence.
2022-06-01

9570 Background: Clinical trials demonstrated a significantly improved recurrence-free survival (RFS) of melanoma patients treated adjuvantly with immune checkpoint inhibition (ICI) and targeted therapy (TT). As data from controlled trials are based on selected populations, we investigated melanoma patients with high risk of recurrence who opted for ICI, TT, or no adjuvant treatment (NoTx) under real-world conditions. Methods: In a prior analysis of this multicenter, retrospective cohort study, patients with resected melanoma stage III-IV between 06/2018 and 09/2019 were analyzed for adjuvant therapy choice (Lodde et al., Cancers 2021). In this follow-up study, the treatment course of ICI- and TT-treated patients as well as recurrence characteristics, subsequent management and outcomes also including NoTx patients were examined. Results: 814 patients were included (72 stage IIIA, 266 IIIB, 383 IIIC, 24 IIID, 69 IV; 309 BRAF mut); 533 patients received ICI (66%), 114 TT (14%, 36.9% of all BRAF mutated patients), 167 patients had opted for NoTx (21%). Median treatment duration was 10.2 and 11.7 months for ICI and TT, respectively. ICI was discontinued prematurely in 51% (273/533) and TT in 44% (50/114) of patients. The main reason for discontinuation was progressive disease (PD) in ICI patients (58%, 158/273) and adverse events in TT patients (60%, 33/50). At a median follow-up (FU) of 24.6 months for ICI, 25.3 months for TT, and 21.8 months for NoTx, 48% of ICI (255/533), 35% of TT (40/114), and 45% of NoTx (75/167) patients had developed a recurrence mostly at distant sites (ICI 62%, TT 63%, NoTx 64%). In patients with recurrence, median time from start of adjuvant treatment to 1 st recurrence was 6.1 months in ICI and 17.6 months in TT. Median RFS was 32.0 months for ICI (95% CI 25.7-38.3), not reached for TT, and 22.3 months for NoTx (95% CI 15.2-29.4). Among BRAF mut patients with stage III, risk of recurrence was higher for ICI than TT (hazard ratio adjusted for age, sex and tumor stage, 2.31; 95% CI 1.56-3.43). Subsequent systemic treatment for the 1 st recurrence was given in 76% (192/253) of ICI, 83% (33/40) of TT, and 53% (40/75) of NoTx patients. Among patients who received the 1 st subsequent systemic treatment for metastatic disease, PD was the best response in 67% (82/123) for ICI, 55% (11/20) for TT, and 50% (16/32) for NoTX. Conclusions: After 2 years of FU, recurrences were mostly at distant sites in all groups. ICI had higher discontinuation rates and more and earlier recurrences than TT. BRAF mut melanoma patients treated with ICI had a significantly higher risk of relapse than TT-treated patients. Response to subsequent systemic treatment was low for both ICI and TT.
Further evidence for Cretaceous wildfires: macro-charcoal from the Malha Formation at Wadi Budra, west-central Sinai, Egypt
2022-06-01

Abstract Fossil evidence for wildfires, in form of fossil charcoal, is known from a large number of Cretaceous localities worldwide and it has repeatedly been argued that wildfires were connected to the evolution and radiation of angiosperms during this period. The present study provides new evidence (in form of macro-charcoal) for the occurrence of wildfires during deposition of the Lower Cretaceous (pre-Aptian) Malha Formation at Wadi Budra of the Sinai Peninsula, Egypt. Despite growing evidence for the worldwide occurrence of wildfires during the Cretaceous, the available database for pre-Aptian wildfires is still rather scarce for large regions when seen on a global scale, hampering causal interpretations concerning the interactions between fire ecology and the evolution of ecosystems during these stages.
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426.
2022-06-01

4513 Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) met its primary and key secondary end points of improved OS, PFS, and ORR with pembro + axi versus sunitinib as first-line treatment for patients with advanced ccRCC. Extended follow-up (42.8-mo median follow-up) continued to show the superior efficacy of pembro + axi versus sunitinib in this patient population. We describe the results of PFS2 for all randomly assigned patients and across IMDC risk categories. Methods: Treatment-naive patients with advanced ccRCC, Karnofsky Performance Status Scale score ≥70% and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 doses (̃2 y) + axi 5 mg orally twice daily or sunitinib 50 mg orally once daily on a 4-wk on/2-wk off schedule. The end point of this exploratory analysis was PFS2, defined as time from randomization to progression after first subsequent therapy or any-cause death. The Kaplan-Meier method was used to estimate PFS2 and hazard ratios were estimated using a Cox regression model. Results: Of 861 patients, 432 were assigned to receive pembro + axi; 429, to sunitinib. Median time from randomization to the database cutoff date (January 11, 2021) was 42.8 mo (range, 35.6-50.6). Overall, 47.2% of patients (204/432) in the pembro + axi arm and 65.5% of patients (281/429) in the sunitinib arm received ≥1 line of subsequent anticancer therapy. For patients who received subsequent therapy, anti–PD-1/PD-L1 agents were the first subsequent treatment for 11.3% of patients (23/204) in the pembro + axi arm and 54.8% of patients (154/281) in the sunitinib arm. In the pembro + axi arm, 82.8% of patients (169/204) received a VEGF/VEGFR inhibitor as first subsequent therapy, as did 43.4% (122/281) in the sunitinib arm. PFS2 results are displayed in the Table. Conclusions: In this exploratory analysis, PFS2 was longer for patients randomized to pembro + axi compared to sunitinib. Results were consistent across IMDC risk groups. These data support use of pembro + axi for the first-line treatment of patients with advanced ccRCC. Clinical trial information: NCT02853331. [Table: see text]
Health-related quality of life in patients with relapsed/refractory multiple myeloma (RRMM) treated with teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody: Patient-reported outcomes in MajesTEC-1.
2022-06-01

8033 Background: As multiple myeloma (MM) negatively affects patients’ (pts) health-related quality of life (HRQoL), assessment of patient-reported outcomes (PROs) in addition to clinical outcomes is important. Teclistamab (tec; JNJ-64007957) is an off-the-shelf bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing MM cells. Initial results from the pivotal cohort of the phase 1/2 MajesTEC-1 study demonstrated that tec was well tolerated with encouraging efficacy in pts who received ≥3 prior lines of treatment (LOT; including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody). Here we report PROs from this cohort. Methods: Pts (aged ≥18 years) had documented RRMM (International Myeloma Working Group criteria), progressive/measurable disease, and had previously received ≥3 prior LOT; prior anti-BCMA treatment (tx) was not allowed. Pts received weekly subcutaneous tec at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PROs were assessed at screening and every even cycle (cycles 2–8 reported here) using the EORTC QLQ-C30 (range: 0–100; higher scores indicate better global health status [GHS] but greater symptom severity [symptom scales]) and the EuroQol 5-dimensional descriptive system (visual analog scale [VAS] range: 0 [worst imaginable health state] to 100 [best imaginable]). Tx effect was assessed by a mixed-effects model with repeated measures; the proportion of pts with meaningful improvement was defined as a change ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: A total of 110 pts were included (median follow-up: 7.8 mos). Overall PRO compliance rates were high (baseline [BL]: 85–90%; cycles 2–8: 80–94%). Tec improved overall HRQoL as evidenced by improvements in GHS scores (cycles 2–8) and reduction in pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall change in physical functioning and fatigue. The proportions of pts with meaningful improvements from BL at cycle 8 were GHS: 50%; physical functioning: 35%; pain: 65%; fatigue: 73%; 50% of pts reported meaningful improvement in their overall health (VAS). Median time to improvement from baseline was ̃1.5 months (with nausea/vomiting and fatigue taking longer to improve), while median time to worsening (all symptoms) ranged from 2 months to not estimable. Conclusions: Consistent with clinical outcomes, pts treated with tec reported rapid, clinically meaningful improvements in HRQoL. Clinical trial information: NCT04557098. [Table: see text]
Easy efficient HDR-based targeted knock-in in Saccharomyces cerevisiae genome using CRISPR-Cas9 system
2022-06-01

During the last two decades, yeast has been used as a biological tool to produce various small molecules, biofuels, etc., using an inexpensive bioprocess. The application of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein (Cas) techniques in yeast genetic and metabolic engineering has made a paradigm shift, particularly with a significant improvement in targeted chromosomal integration using synthetic donor constructs, which was previously a challenge. This study reports the CRISPR-Cas9-based highly efficient strategy for targeted chromosomal integration and in-frame expression of a foreign gene in the genome of <i>Saccharomyces cerevisiae</i> (<i>S. cerevisiae</i>) by homology-dependent recombination (HDR); our optimized methods show that CRISPR-Cas9-based chromosomal targeted integration of small constructs at multiple target sites of the yeast genome can be achieved with an efficiency of 74%. Our study also suggests that 15 bp microhomology flanked arms are sufficient for 50% targeted knock-in at minimal knock-in construct concentration. Whole-genome sequencing confirmed that there is no off-target effect. This study provides a comprehensive and streamlined protocol that will support the targeted integration of essential genes into the yeast genome for synthetic biology and other industrial purposes.<b>Highlights</b><b>•</b> CRISPR-Cas9 based in-frame expression of foreign protein in <i>Saccharomyces cerevisiae</i> using Homology arm without a promoter.<b>•</b> As low as 15 base pairs of microhomology (HDR) are sufficient for targeted integration in <i>Saccharomyces cerevisiae</i>.<b>•</b> The methodology is highly efficient and very specific as no off-targeted effects were shown by the whole-genome sequence.
A new tool for bile duct tissue sampling: ex vivo clinical evaluation of intraductal cryobiopsy for cholangioscopy
2022-06-01

Abstract Background and study aims Indeterminate biliary strictures represent a major challenge in clinical diagnostics. Diagnostic yield of radiological, endoscopic imaging and histopathological diagnosis is insufficient. The cryobiopsy technique is a new method for tissue extraction already used in different clinical settings. The aim of this ex vivo clinical study was to investigate feasibility and tissue quality of cryobiopsy in the bile duct. Patients and methods We included 14 patients who underwent pancreaticoduodenectomy. Bile duct samples were taken with either a new prototype cryoprobe or one of two forceps types. Results were analyzed for general feasibility, specimen size, histological assessability as well as representativity of retrieved tissue. Results Feasibility of cholangioscopic forceps was poor compared to gastric biopsy forceps or cryobiopsy. Significantly larger tissue samples were obtained with cryobiopsy (5.6 ± 4.5 mm2) compared to gastric biopsy forceps (3.3 ± 5.1 mm2, P = 0.006). Furthermore, cryobiopsy was superior in histological assessment quality (P = 0.02) and concerning representativity (P = 0.03). Conclusions Cryobiopsy in the bile duct is feasible and the quality of the obtained tissue is high. Further investigation of bile duct cryobiopsy in vivo is warranted.
Multihit Injury of the Radial Nerve in a 62-year-old Woman: A Case Report
2022-06-01

Summary: We report the case of a 62-year-old female patient with a triple-crush radial nerve injury, diagnosed in subsequent order following a fracture of the left humerus. The patient developed flaccid paralysis of all muscles innervated by the left radial nerve except the triceps brachii and reported a sensory deficit corresponding to the innervation territories of the posterior nerve of the forearm as well as the superficial branch of the radial nerve. Following neurolysis of the radial nerve at the humerus level, wrist extension as well as sensory perception on the dorsal aspect of the forearm recovered, but finger extension and thumb abduction were still impossible. Following neurological evaluation and nerve ultrasound, supinator syndrome was diagnosed and the patient underwent decompression surgery. Following surgical decompression, motor recovery was observable but a sensory deficit remained in the area innervated by the superficial branch of the radial nerve. In consequence, the third crush injury of the left radial nerve, that is, Wartenberg syndrome or cheiralgia paraesthetica was diagnosed. Decompression surgery of the superficial branch of the radial nerve was performed and the patient reported profound amelioration of her sensory symptoms during a follow-up examination at our outpatient clinic 6 weeks postoperatively.
Spatial Markov Model for the Prediction of Travel‐Time‐Based Solute Dispersion in Three‐Dimensional Heterogeneous Media
2022-06-01

Abstract In recent years, Spatial Markov Models have gained popularity in simulating solute transport in heterogeneous formations. They describe the transition times of particles between equidistant observation planes by statistical distributions, assuming correlation of the transit times of individual particles between subsequent steps. By this, the approach naturally captures preasymptotic solute dispersion. In this study, we analyze Spatial Markov Models assuming bivariate log‐normal distributions of the particle slowness (i.e., the inverse velocity) in subsequent transitions. The model is fully parameterized by the mean Eulerian velocity, the variance of the log‐slowness, and the correlation coefficient of log‐slowness in subsequent steps. We derive closed‐form expressions for distance‐dependent ensemble dispersion, which is defined in terms of the second‐central moments of the solute breakthrough curves. We relate the coefficients to the properties of the underlying log‐hydraulic conductivity field assuming second‐order stationarity. The results are consistent with linear stochastic theory in the limit of small log‐conductivity variances, while the approach naturally extends to high‐variance cases. We demonstrate the validity of the approach by comparison to three‐dimensional particle‐tracking simulations of advective transport in heterogeneous media with isotropic, exponential correlation structure for log‐conductivity variances up to five. This study contributes to relating solute dispersion to metrics of the porous‐medium structure in cases of strong heterogeneity.
Metronomic oral maintenance chemotherapy in patients with localized high-risk rhabdomyosarcoma (RMS) and RMS-like tumors: A report from a randomized, multicenter, phase III trial CWS-2007HR.
2022-06-01

10033 Background: Low dose maintenance therapy as consolidation after multimodal standard therapy has been shown to improve survival in patients with sarcoma. It is however unclear which drugs and how long would be optimal. We investigated whether adding oral maintenance chemotherapy after standard multimodal therapy (ST) in patients with localized RMS and RMS-like sarcoma defined as high and very-high risk (HR and VHR), according to CWS stratification, would improve survival. Methods: Patients (pts) age &gt; 6 months &lt; 21 years, with 1. embryonal RMS N0, incompletely resected, (Group II or III), tumor size &gt; 5cm and/or ≥10 years, in unfavorable primary sites and all N1 (HR RMS Group), 2. alveolar RMS N0/N1 (VHR RMS Group) 3.Unidfferentiated sarcoma (UDS), extraskeletal Ewing sarcoma (EES) and primary non resectable (Group III) synovial sarcoma (SS) (HR RMS-like Group) in complete remission after ST including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (S-arm) or receive maintenance chemotherapy (M-arm) with eight 10-days courses consisting of trofosfamide (2x 75mg/m2/day) and idarubicine (1 x 5mg/m2/day 1,4,7,10) alternating with trofosfamide and etoposide (2x 25mg/m2/day). The study was designed with 80% power and a two-sided alpha level of 5% to detect an increase in 3 yr EFS from 60 to 75%. Randomisation was stratified according to risk groups. To reduce possible imbalances in the number of treatment assignments, a permuted block design was used. The initial calculated sample size was 145 pts in each group (recruitment period six years). Due to the lower than planned recruitement rate, the accrual was extended to 10 years and sample size recalculated to 98 pts in each group. Results: Between 1.7.2009 and 30.6.2019, 441 pts were eligible at diagnosis and 337 at the end of ST. 195 pts were randomized: 99 were assigned to the S-arm and 96 to M-arm. The distribution of the following clinical features:age, gender, tumor size, IRS-Group, T-Status, N-Status, histology and localisation showed no significant difference between the treatment groups. In the intent to treat population, with a median follow up of 4.9 years (IQR 3.0-5.7) in surviving pts, 3yr EFS and OS in M-arm vs S-arm were respectively: EFS 66.2% (95% IC 57.1-76.79) vs 75.0% (95% IC 66.8-84.3) (p 0.07) and OS 81.9% (95% IC 74.2-90.4) vs 84.6 (95% IC 77.5-92.4) (p 0.15). Toxicity grade 3 (no grade 4) in the M-arm was: hematological in 51 %, febrile infection 5%, sensory neuropathy in 1% pts. Conclusions: The addition of maintenance therapy with trofosfamide, etoposide and idarubicine after ST does not improve EFS and OS in patients with high risk RMS and RMS-like sarcomas. Clinical trial information: 2007-0001478-10.
Thermobiological effects of temperature‐induced color variations inAglais urticae(Lepidoptera, Nymphalidae)
2022-06-01

Abstract Coloration of animals is important for camouflage, for social behavior, or for physiological fitness. This study investigates the color variation in adults of Aglais urticae obtained on subjecting some pre‐imaginal stages to different temperature conditions and their thermobiological consequences. To investigate the evolutionary–ecological interactions of temperature and pigmentation in butterflies, caterpillars, and pupae of the small tortoiseshell, Aglais urticae (Lepidoptera, Nymphalidae), larvae from Central Europe and Scandinavia were reared at temperatures between 7 and 34°C in the laboratory or in the field. After emergence, the intensity of pigmentation of the imagines and their increase in body temperature under defined full‐spectrum light irradiation were quantified by image analysis and thermal imaging. At constant conditions, ambient rearing temperature and pigmentation intensity of imagines were negatively and linearly correlated in Central European butterflies, regardless of whether the pupal stage alone or, additionally, the last period of the larval stage was exposed to these conditions: low temperatures induced darker coloration and high temperatures led to lighter individuals. A thermal pulse of a few days alone at the beginning of pupal dormancy led to a similar, albeit weakened, effect. Caterpillars of the Scandinavian subspecies A . urticae polaris , whose pupal dormancy took place under Central European field conditions, developed into strongly pigmented imagines. The thermobiological relevance of more intense pigmentation was shown by significantly higher absorption of light, and thus stronger increased body temperature after 5 min of defined illumination, but this difference ceased after 15 min. Our results show that phenotypic plasticity in wing coloration is adaptive since temperature‐induced developmental changes provide thermobiological benefit in adult butterflies. We propose that, in subpolar latitudes, darker coloration likely has a selection advantage favoring individuals with reaction norms gradually shifted to stronger pigmented phenotypes, possibly leading to the establishment of a pigmentation cline.
Clinical outcomes and safety of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) in patients aged < 75 and ≥ 75 years: ARCHES post hoc analysis.
2022-06-01

5069 Background: Patients with metastatic prostate cancer aged ≥75 years have a poorer prognosis compared with younger patients. In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints vs. placebo (PBO) + ADT in patients with mHSPC. Final OS results confirmed a long-term survival benefit with ENZA + ADT. This post hoc analysis of ARCHES data investigated OS and other clinical outcomes in patients aged &lt;75 and ≥75 years. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. Subgroup analysis was performed in patients aged &lt;75 and ≥75 years. Efficacy and safety outcomes were compared across treatment arms. Results: Of the ARCHES population, 339 patients (29.5%) were aged ≥75 years (ENZA + ADT, n=170; PBO + ADT, n=169); PBO patients crossing over to ENZA were aged: &lt;75 years, n=133; ≥75 years, n=47. Some differences in baseline characteristics were observed between age groups, such as higher prior docetaxel use in patients aged &lt;75 years (ENZA + ADT, 21.0%; PBO + ADT, 20.4%) vs. those aged ≥75 years (ENZA + ADT, 10.6%; PBO + ADT, 11.2%). When compared to PBO + ADT, ENZA + ADT improved OS and other secondary efficacy endpoints in both age groups without evidence of statistical heterogeneity (Table); however, 95% confidence intervals for OS and rPFS hazard ratios spanned 1 in the older age group. The safety profile of treatment arms was generally similar in both age groups, with a higher incidence of falls, cognitive impairment, and cardiovascular events among elderly patients receiving ENZA + ADT vs. PBO + ADT. Conclusions: This post hoc analysis of ARCHES data demonstrated that ENZA + ADT provides clinical benefit and is generally well-tolerated in patients with mHSPC aged ≥75 years, supporting the therapeutic role of ENZA in these patients. Clinical trial information: NCT02677896. [Table: see text]
Uniform Priors for Data-Efficient Learning
2022-06-01

Few or zero-shot adaptation to novel tasks is important for the scalability and deployment of machine learning models. It is therefore crucial to find properties that encourage more transferable features in deep networks for generalization. In this paper, we show that models that learn uniformly distributed features from the training data, are able to perform better transfer learning at test-time. Motivated by this, we evaluate our method: uniformity regularization (UR) on its ability to facilitate adaptation to unseen tasks and data on six distinct domains: Few-Learning with Images, Few-shot Learning with Language, Deep Metric Learning, 0-Shot Domain Adaptation, Out-of-Distribution classification, and Neural Radiance Fields. Across all experiments, we show that using UR, we are able to learn robust vision systems which consistently offer benefits over baselines trained without uniformity regularization and are able to achieve state-of-the-art performance in Deep Metric Learning, Few-shot learning with images and language.