bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant pembrolizumab plus chemotherapy/adjuvant pembrolizumab for early-stage triple-negative breast cancer: quality-of-life results from the randomized KEYNOTE-522 study
Authors: Dent Rebecca , Cortés Javier , Pusztai Lajos , McArthur Heather , Kümmel Sherko , Bergh Jonas , Denkert Carsten , Park Yeon Hee , Hui Rina , Harbeck Nadia , Takahashi Masato , Untch Michael , Fasching Peter A , Cardoso Fatima , Haiderali Amin , Jia Liyi , Nguyen Allison Martin , Pan Wilbur , O’Shaughnessy Joyce , Schmid Peter 
Published: June 2024

Abstract

Background
In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522.

Methods
Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned).

Results
Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were −1.04 (95% confidence interval = −3.46 to 1.38), −0.69 (95% CI = −3.13 to 1.75), and −2.85 (95% CI = −5.11 to −0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were −0.41 (95% CI = −2.60 to 1.77), −0.60 (95% CI = −2.99 to 1.79), and −1.57 (95% CI = −3.36 to 0.21).

Conclusions
No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC.

Trial registration
ClinicalTrials.gov, NCT03036488.
Effect of smoking on melanoma incidence: a systematic review with meta-analysis
Authors: Friedman Erica B , Williams Gabrielle J , Lo Serigne N , Thompson John F 
Published: June 2024

Abstract

Background
There is a strong correlation between cigarette smoking and the development of many cancer types. It is therefore paradoxical that multiple reports have suggested a reduced incidence of melanoma in smokers. This study aimed to analyze all existing studies of melanoma incidence in smokers relative to nonsmokers.

Methods
Searches of MEDLINE and Embase were conducted for studies reporting data on melanoma in smokers and never-smokers. No study design limitations or language restrictions were applied. The outcome examined was the association between smoking status and melanoma. Analyses focused on risk of melanoma in smokers and never-smokers generated from multivariable analyses, and these analyses were pooled using a fixed-effects model. Risk of bias was assessed using the Newcastle-Ottawa tool.

Results
Forty-nine studies that included 59 429 patients with melanoma were identified. Pooled analyses showed statistically significant reduced risks of melanoma in male smokers (risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.56 to 0.65, P &lt; .001) and female smokers (RR = 0.79, 95% CI = 0.73 to 0.86, P &lt; .001). Male former smokers had a 16% reduction in melanoma risk compared with male never-smokers (RR = 0.84, 95% CI = 0.77 to 0.93, P &lt; .001), but no risk reduction was observed in female former smokers (RR = 1.0, 95% CI = 0.92 to 1.08).

Conclusions
Current smokers have a statistically significant reduced risk of developing melanoma compared with never-smokers, with a reduction in melanoma risk of 40% in men and 21% in women.
A case report on the management of neglected and forgotten DJ stent for 18 years with severe encrustation and giant bladder stone
Authors: Nigusie Alemu Tsiyon , Aderaw Habtamu , Sheiferawe Yacob , Tsehaye Kinfe 
Published: June 2024

Abstract
Ureteral stents play a vital role in urologic surgeries, aiding in urinary flow maintenance, obstruction alleviation and facilitating healing. However, when stents are forgotten, they can lead to encrustation, resulting in significant patient morbidity and posing challenges for urologists Stent-related complications have been shown to increase with the duration of time the stent is left in place. This report details the clinical presentation, diagnostic process, and treatment of a 68-year-old male patient had a neglected stent placed 18 years ago after extracorporeal shockwave lithotripsy. He presented with severe stent encrustation, a solitary giant bladder stone, and renal stones. The patient underwent a cystolithotomy to remove the bladder stone followed by an ultrasound-guided percutaneous nephrolithotomy with pneumatic lithotripsy in a separate procedure. Preventive strategies such as implementing a stent registry, enhancing patient education, and encouraging follow-up appointments are crucial to avoid such complications.
Prey Shifts Drive Venom Evolution in Cone Snails
Authors: Koch Thomas Lund , Robinson Samuel D , Salcedo Paula Flórez , Chase Kevin , Biggs Jason , Fedosov Alexander E , Yandell Mark , Olivera Baldomero M , Safavi-Hemami Helena 
Published: June 2024

Abstract
Venom systems are complex traits that have independently emerged multiple times in diverse plant and animal phyla. Within each venomous lineage there typically exists interspecific variation in venom composition where several factors have been proposed as drivers of variation, including phylogeny and diet. Understanding these factors is of broad biological interest and has implications for the development of antivenom therapies and venom-based drug discovery. Because of their high species richness and the presence of several major evolutionary prey shifts, venomous marine cone snails (genus Conus) provide an ideal system to investigate drivers of interspecific venom variation. Here, by analyzing the venom gland expression profiles of ∼3,000 toxin genes from 42 species of cone snail, we elucidate the role of prey-specific selection pressures in shaping venom variation. By analyzing overall venom composition and individual toxin structures, we demonstrate that the shifts from vermivory to piscivory in Conus are complemented by distinct changes in venom composition independent of phylogeny. In vivo injections of venom from piscivorous cone snails in fish further showed a higher potency compared with venom of nonpiscivores demonstrating a selective advantage. Together, our findings provide compelling evidence for the role of prey shifts in directing the venom composition of cone snails and expand our understanding of the mechanisms of venom variation and diversification.
No benefit from TMZ treatment in glioblastoma with truly unmethylated MGMT promoter: Reanalysis of the CE.6 and the pooled Nordic/NOA-08 trials in elderly glioblastoma patients
Authors: Hegi Monika E , Oppong Felix B , Perry James R , Wick Wolfgang , Henriksson Roger , Laperriere Norman J , Gorlia Thierry , Malmström Annika , Weller Michael 
Published: June 2024

Abstract

Background
The treatment of elderly/ frail patients with glioblastoma is a balance between avoiding undue toxicity, while not withholding effective treatment. It remains debated, whether these patients should receive combined chemo-radiotherapy with temozolomide (RT/TMZ→TMZ) regardless of the O6-methylguanine DNA methyltransferase gene promoter (MGMTp) methylation status. MGMT is a well-known resistance factor blunting the treatment effect of TMZ, by repairing the most genotoxic lesion. Epigenetic silencing of the MGMTp sensitizes glioblastoma to TMZ. For risk-adapted treatment, it is of utmost importance to accurately identify patients, who will not benefit from TMZ treatment.

Methods
Here, we present a reanalysis of the clinical trials CE.6 and the pooled NOA-08 and Nordic trials in elderly glioblastoma patients that compared RT to RT/TMZ→TMZ, or RT to TMZ, respectively. For 687 patients with available MGMTp methylation data, we applied a cutoff discerning truly unmethylated glioblastoma, established in a pooled analysis of 4 clinical trials for glioblastoma, with RT/TMZ→TMZ treatment, using the same quantitative methylation-specific MGMTp PCR assay.

Results
When applying this restricted cutoff to the elderly patient population, we confirmed that glioblastoma with truly unmethylated MGMTp derived no benefit from TMZ treatment. In the Nordic/NOA-08 trials, RT was better than TMZ, suggesting little or no benefit from TMZ.

Conclusions
For evidence-based treatment of glioblastoma patients validated MGMTp methylation assays should be used that accurately identify truly unmethylated patients. Respective stratified management of patients will reduce toxicity without compromising outcomes and allow testing of more promising treatment options.
Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies
Authors: Sönksen Marthe , Obrecht-Sturm Denise , Hernáiz Driever Pablo , Sauerbrey Axel , Graf Norbert , Kontny Udo , Reimann Christian , Langhein Mina , Kordes Uwe R , Schwarz Rudolf , Obser Tobias , Boschann Felix , Schüller Ulrich , Altendorf Lea , Goschzik Tobias , Pietsch Torsten , Mynarek Martin , Rutkowski Stefan 
Published: June 2024

Abstract

Background
The outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims to give a comprehensive overview of clinical and molecular characteristics of pediatric FA MB patients.

Methods
Clinical data including detailed information on the treatment and toxicities of 6 previously unreported FA MB patients were supplemented with data of 16 published cases.

Results
We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n = 9), confirmed by methylation profiling in 5 patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n = 16) or FA-N (n = 3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT) ± chemotherapy (27%). Of 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI: 0.3–1.8). 1-year-progression-free-survival (PFS) was 26.3% ± 10.1% and 1-year-OS was 42.1% ± 11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3% ± 12.9%/33.3 ± 12.2% with adjuvant therapy, P = .006/P = .086).

Conclusions
MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.
Crossing the Ludo-Cinematic Continuum
Authors: Atkinson Sean 
Published: June 2024

Abstract
Sean Atkinson outlines three challenges faced when applying western music theory to the analysis of video game music: the theory was developed to analyze western art music; video game music is an art form that makes use of such art music but that also makes use of other musics; and the interactivity of video game music is a specific problem that must be accounted for. Regarding this last, and concentrating on the link to film music, Atkinson presents a ludo-cinematic continuum model that describes not the video game music itself but rather its function and use in the game. Thus, music with a more ludic function is more interactive and less choreographed compared to the scripted and choreographed cinematic function. In using the model to conduct a preliminary assessment of the music to be analyzed, Atkinson provides the means to determine the most appropriate analytical tools when it comes to the music itself.
Ambient Ecologies
Authors: Kamp Michiel 
Published: June 2024

Abstract
In a chapter on ambient ecologies of music in video games, Michiel Kamp argues for including nondynamic musical cues as part of the ecology of the game. Such music, unlike the dynamic music that is typically the subject of much academic discourse and media attention, provides no ludic signals about the gameplay state; it is an ambient cue that is “just there.” Kamp argues that, far from being dismissed as mere background music, this ambient music is a key part of the ecology of the game, providing stability and persistence and a space within which to achieve the game’s goals.
Ode to Joysticks
Authors: Gibbons William 
Published: June 2024

Abstract
On the back of the 2020 Game Awards recognition of that year’s Final Fantasy VII Remake in the “Best Score and Music” category, William Gibbons explores the meaning of labels such as “the Beethoven of game music” applied to the composer Nobuo Uematsu. Gibbons is concerned with our understanding of Uematsu’s place in music history, but more generally in how and why these labels develop in music history, as well as how they shape audience perceptions of musical value over time. Cycles of canonization emphasizing one composer as exceptional risk overshadowing the relevance and importance of other video game music composers.
A History of Early US Pinball Sound, 1871–1939
Authors: Lerner Neil 
Published: June 2024

Abstract
Neil Lerner explores the roots of video game sound practices through an investigation of the sound of US pinball machines from 1871 to 1939. Lerner suggests that pinball and its predecessors always had sound as an element of play. Along with the introduction of electromechanical sound-producing devices in 1934 (Harry Williams’ Contact), this established several conventions of sounds in games that influenced the early video game designers in the 1970s, several of whom worked for companies that had originally been pinball manufacturers. In 1935, Big Game became the first pinball machine to include a sound effect intended to increase the realism of the theme; in this case, it was a synchronizing of a light and a quickly struck metal plate that simulated a gunshot. Bells remained the principal sound in pinball machines until the solid-state era began in the 1970s.
The fine-tuning argument against the multiverse
Authors: Boyce Kenneth , Swenson Philip 
Published: June 2024

Abstract
It is commonly argued that the fact that our universe is fine-tuned for life favors both a design hypothesis as well as a non-teleological multiverse hypothesis. The claim that the fine-tuning of this universe supports a non-teleological multiverse hypothesis has been forcefully challenged however by Ian Hacking and Roger White. In this paper we take this challenge even further by arguing that if it succeeds, then not only does the fine-tuning of this universe fail to support a multiverse hypothesis, but it tends to favor a single-universe hypothesis instead.
Poverty Governance in the Delegated Welfare State: Privatization, Commodification, and the U.S. Health Care Safety Net
Authors: Parker Emily 
Published: June 2024

Abstract
Due to forces of retrenchment and fiscal austerity in the contemporary U.S. welfare state, the federal government has increasingly delegated the funding of public programs to private entities. How does privatization influence the way marginalized populations experience the social safety net? To develop insights on delegated poverty governance, this study examines a longstanding public-private program—Federally Qualified Health Centers (FQHCs)—which comprise a nationwide network of clinics serving over thirty million predominantly low-income patients in medically underserved areas. I conducted a case study drawing on in-depth interviews with patients and staff in a small-town FQHC in the Rust Belt. Unlike other social welfare programs, I found a pronounced absence of stigma associated with the FQHC, largely due to features of the delegated policy design, the blended institutional setting, and strategic organizational decisions. However, low-income patients were also unaware of their rights to treatment when encountering paternalistic enforcement of overdue billing rules, which resulted in delayed or foregone health care. Due to underlying tensions surrounding commodification, I argue that privatization of the safety net may quell the stigma of government programs among the poor while simultaneously disentitling individuals from their rights of social citizenship.
Evaluation of significantly changed chemokine factors of idiopathic granulomatous mastitis in non‐puerperal patients
Authors: Li Fangyuan , Nie Longzhu , Huang Junying , Sin Tat‐Hang , Wang Xuejing , Zhang Fan , Ma Jia , Shi Xiaoguang , Chen Linlin , Niu Kunying , Zhang Xiaohui , Zhou Yidong 
Published: June 2024

AbstractIdiopathic granulomatous mastitis (IGM), a recurrent inflammation disease of the non‐lactating breast, has had an increasing clinical morbidity rate in recent years, and its complicated symptoms and unclear etiology make it challenging to treat. This rare benign inflammatory breast disease, centered on the lobules, represents the most challenging type of non‐puerperal mastitis (NPM), also known as non‐lactating mastitis. In this study, patients diagnosed with IGM (M, n = 23) were recruited as cases, and patients with benign control breast disease (C, n = 17) were enrolled as controls. Cytokine microarray detection measured and analyzed the differentially expressed cytokine factors between IGM and control patients. Then, we verified the mRNA and protein expression levels of the significantly changed cytokine factors using Q‐RT‐PCR, ELISA, western blot, and IHC experiments. The cytokine factor expression levels significantly changed compared to the control group. We observed a significant increase between IGM and control patients in cytokine factors expression, such as interleukin‐1β (IL‐1β), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)‐1α, MIP‐1β, tumor necrosis factor receptor 2 (TNF RII). Then, we verified the expression of these top five dysregulated factors in both mRNA and protein levels. Our results demonstrated the cytokine map in IGM and indicated that several cytokines, especially chemokines, were associated with and significantly dysregulated in IGM tissues compared to the control group. The chemokine factors involved might be essential in developing and treating IGM. These findings would be helpful for a better understanding of IGM and offer valuable insights for devising novel diagnostic and therapeutic strategies.
Food poisoning due to money tree seeds: a case report of toxic encephalopathy
Authors: Zhao Yue , Quan Xiaojiao , Wang Tao 
Published: June 2024

Abstract

Background
The money tree is a favored indoor potted plant in China. Its seeds resemble chestnuts in both shape and flavor when cooked, which are generally considered non-toxic and safe for consumption.

Case presentation
This report presents the first published case of food poisoning due to the ingestion of large amounts of money tree seeds. A 67-year-old man exhibited toxic encephalopathy symptoms and dyspnea after consuming the seeds for approximately 6 months. After empirical mechanical ventilation, therapeutic plasma exchange, and other medical interventions, the patient’s clinical status improved significantly. He was subsequently discharged from the hospital.

Conclusion
Consuming a substantial quantity of money tree seeds within a limited timeframe can lead to poisoning, resulting in adverse outcomes, particularly toxic encephalopathy. Moreover, plasma exchange may have some therapeutic effect.
Associations of Local Cannabis Control Policies With Harmful Cannabis Exposures Reported to the California Poison Control System
Authors: Matthay Ellicott C. , Mousli Leyla M. , Sun Chloe , Lewis Justin , Jacobs Laurie M. , Heard Stuart , Ho Raymond , Schmidt Laura A. , Apollonio Dorie E. 
Published: June 2024

Background:Cannabis exposures reported to the California Poison Control System increased following the initiation of recreational cannabis sales on 1 January 2018 (i.e., “commercialization”). We evaluated whether local cannabis control policies adopted by 2021 were associated with shifts in harmful cannabis exposures.Methods:Using cannabis control policies collected for all 539 California cities and counties in 2020–2021, we applied a differences-in-differences design with negative binomial regression to test the association of policies with harmful cannabis exposures reported to California Poison Control System (2011–2020), before and after commercialization. We considered three policy categories: bans on storefront recreational retail cannabis businesses, overall restrictiveness, and specific recommended provisions (restricting product types or potency, packaging and labeling restrictions, and server training requirements).Results:Localities that ultimately banned storefront recreational retail cannabis businesses had fewer harmful cannabis exposures for children aged <13 years (rate ratio = 0.82; 95% confidence interval = 0.65, 1.02), but not for people aged >13 years (rate ratio = 0.97; 95% confidence interval = 0.85, 1.11). Of 167 localities ultimately permitting recreational cannabis sales, overall restrictiveness was not associated with harmful cannabis exposures among children aged <13 years, but for people aged >13 years, a 1-standard deviation increase in ultimate restrictiveness was associated with fewer harmful cannabis exposures (rate ratio = 0.93; 95% confidence interval = 0.86, 1.01). For recommended provisions, estimates were generally too imprecise to detect associations with harmful cannabis exposures.Conclusion:Bans on storefront retail and other restrictive approaches to regulating recreational cannabis may be associated with fewer harmful cannabis exposures for some age groups following statewide commercialization.