bluuebunny/crossref_metadata_2025 huggingface dataset:
Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models
Authors: Awasthi Niranjan , Darman Lily , Schwarz Margaret A. , Schwarz Roderich E.
Published: September 2024

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5‐year survival rate of 5%–15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12–14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab‐paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%–53%) compared to NPT (56%–69%) or GemCis (37%–58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell‐derived xenografts (67%–90%). PDX studies revealed TE's marked inhibition of tumour growth (40%–73%) compared to GemCis (80%–86%) or NPT (57%–76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.
Paediatric trigger thumb: Diagnostic pearls
Authors: Hudock Nicholas L , Girgis Michael W , Glaun Gabriel D , Hennrikus William L
Published: September 2024

Aim

The purpose of this study is to report diagnostic pearls and review the clinical presentation and outcomes of surgical treatment of paediatric trigger thumbs.

Methods

A retrospective review of medical records and imaging studies was performed on children with trigger thumbs from January 2009 to December 2019.

Results

Sixty‐four trigger thumbs in 52 consecutive patients were treated. The average age at referral was 2.5 years. Symptoms include pain (4), triggering (14) and fixed contracture (38). The average symptom duration was 8 months. Forty patients had been evaluated and referred by a paediatrician or primary care doctor. Twenty‐four of the 52 (46%) patients received hand x‐rays and were initially misdiagnosed as a fracture or dislocation. Physical exam demonstrated a volar nodule in 64 thumbs (100%), fixed flexion deformities in 38 (73%) thumbs and triggering with active extension of the interphalangeal joint in 14 (27%) thumbs. The average age at surgery was 3.2 years. Follow‐up averaged 12 months. Surgery resulted in complete relief of symptoms and correction of deformity. There was no reported loss of function or complication.

Conclusions

Children with trigger thumbs who ultimately undergo surgery present with distinct physical exam findings, including a volar nodule and a fixed flexion contracture. Understanding these pearls can minimise misdiagnosis of the condition as a fracture or dislocation. Highlighting trigger thumbs during musculoskeletal education for paediatric and primary care physicians is recommended. Surgical outcomes were excellent in patients aged 2–8 years old.
Respiratory‐swallow patterning and oropharyngeal swallowing impairment in patients undergoing evaluation for lung transplant
Authors: Graham Kahla , Reedy Erin L. , Lee Jungwha Julia , Norton Elizabeth Spencer , Arunachalam Ambalavanan , Tomic Rade , Martin‐Harris Bonnie
Published: September 2024

Background

Although swallowing impairment is prevalent following lung transplantation, baseline respiratory and swallowing characteristics are often overlooked. Respiratory disease processes may predispose lung transplant candidates to altered respiratory‐swallow patterning and swallowing impairment.

Methods

This cross‐sectional study included patients referred for a Modified Barium Swallow Study during lung transplant evaluation. Swallowing impairment was measured using the Modified Barium Swallow Impairment Profile and Penetration‐Aspiration Scale. Respiratory plethysmographic signals synchronized with videofluoroscopy were analyzed to determine phase patterning, pause duration, and rate. Mixed‐effects logistic regression was used to identify linkages between respiratory and swallowing measures.

Key Results

Fifty patients were included and demonstrated delayed swallow initiation (49/50), oral residue (37/50), incomplete pharyngoesophageal segment opening (35/50), and esophageal retention (43/50). Airway invasion occurred infrequently (10/50). Atypical respiratory patterning was significantly associated with impairment in pharyngeal swallow initiation (OR [95% CI] = 1.76 [1.16, 2.68], p = 0.009), laryngeal elevation (OR [95% CI] = 1.45 [1.01, 2.07], p = 0.044), and laryngeal vestibular closure (OR [95% CI] = 2.57 [1.48, 4.46], p < 0.001). Increased pause duration was associated with impaired initiation (OR [95% CI] = 2.24 [1.20, 4.16], p = 0.011), laryngeal elevation (OR [95% CI] = 1.18 [1.03, 1.36], p = 0.018), laryngeal closure (OR [95% CI] = 1.28 [1.9, 1.50], p = 0.003), and tongue base retraction (OR [95% CI] = 1.33 [1.13, 1.56], p < 0.001).

Conclusions & Inferences

Patients undergoing evaluation for lung transplant demonstrated impaired swallowing and phase patterning. Preliminary findings implicate the need for further evaluation of respiratory‐swallow coordination and its potential role in swallowing impairment before and after lung transplantation.
Preventive and reparative effects of low‐level laser therapy on orthodontically induced inflammatory root resorption—An animal study
Authors: Xu Bowen , Du Rina , Bai Linna , Yang Kai
Published: September 2024

Background

Orthodontically induced inflammatory root resorption (OIIRR) is one of the most important side effects of orthodontic treatment. Low‐level laser therapy (LLLT) is a useful way to reduce the orthodontic treatment duration and may have some effect on preventing and repairing OIIRR. However, the specific effects of LLLT on OIIRR remain unknown.

Objective

Our research aimed to evaluate the Dentin Sialophosphoprotein (DSPP) expression level and root resorption volume during treatment and retention to explore the role of LLLT in preventing and repairing OIIRR.

Methods

Thirty‐seven 6‐week‐old male Sprague–Dawley rats were selected to establish an OIIRR model; the rats were divided into Group B (blank), Group F (force), Group F(LLLT) (force and LLLT), Group F+R (force and retention) and Group F+R(LLLT) (force, retention and LLLT). The root resorption volume of the distal buccal root and mesial root in the maxillary left first molar was calculated by micro‐CT, and the DSPP expression level on the compression side of the periodontal ligament was analysed by immunohistochemical staining.

Results

The resorption volume in Group F was greater than that in Group F(LLLT). For the mesial root, the volume in Group F was greater than that in Groups F+R and F+R(LLLT). For the distal buccal root, the volume in Groups F and F+R was greater than that in Group F+R(LLLT). The DSPP level in Group F(LLLT) was greater than that in Group F and there was no difference between Groups F+R and F+R(LLLT).

Conclusions

LLLT has a certain preventive effect and a limited reparative effect on OIIRR in rats.
Left‐bundle branch optimized CRT implantation in a patient with persistent left superior vena cava
Authors: Gul Enes Elvin , Sodikov Jamshid , Sertdemir Ahmet Lutfu , Yakubov Akmal
Published: September 2024

Persistent left superior vena cava (PLSVC) is one of the anatomical variations, which can make device implantation more challenging and lead to incorrect lead placement, dislodgement, and procedure failure. Conduction system pacing (CSP) can be an alternative to traditional CRT implantation. Herein, we describe a brief case report of successful LBBAP‐optimized CRT (LOT‐CRT) via an innominate vein in a patient with PLSVC.
Dermatoscopic features of vulvar lichen sclerosus in children: A retrospective study
Authors: Han Yuyang , Liu Runtao , Li Yuanjun
Published: September 2024

Objectives

To explore the dermoscopic features of lichen sclerosus in different parts of the external genitalia in children.

Methods

A retrospective analysis of the dermoscopic features of 42 female children with vulvar lichen sclerosus treated in the Department of Dermatology of Shanxi Children's Hospital from January 2020 to May 2023.

Results

Among the 42 female children, aged 3–14 years (mean: 7.24 ± 2.43 years), the duration of vulvar lichen sclerosus ranged from 3 months to 2 years (mean: 9.83 ± 4.93 months). Clinical lesions occurred in the labia minora in 18 cases (42.9%), labia majora in 38 cases (90.5%), posterior fourchette in 36 cases (85.7%), perianal area in 13 cases (31.0%), anterior fourchette in 17 cases (40.5%), clitoris in seven cases (16.7%), and interlabial sulcus in 11 cases (26.2%). Dermoscopic findings common in the labia majora included follicular keratotic plugs, cloverleaf‐like structures, comedo‐like openings, and linear vessels (p < .05); however, purple–red globules and patches and white linear streaks were more common in the posterior fourchette (p < .05), whereas dotted vessels were more common in the labia minora (p < .05).

Conclusions

Common dermoscopic findings in pediatric vulvar lichen sclerosus were yellow‐white structureless areas, white linear streaks, follicular keratotic plugs, and cloverleaf‐like structures; yellow‐white structureless areas and white linear streaks showed the highest specificity. The dermoscopic findings varied among different affected areas, which provides a basis for further understanding of the characteristics of different sites of vulvar lichen sclerosus in the pediatric population.
Trends in adverse effects of medical treatment in Paediatric populations in the United States: A global burden of disease study, 2000–2019
Authors: Fujiwara Shintaro , Leibovitch Emily , Harada Ko , Nishimura Yoshito , Woo Russell , Otsuka Fumio , Bhagavathula Akshaya Srikanth
Published: September 2024

Background

Adverse effects of medical treatment (AEMT) pose significant risks to paediatric patients. However, the mortality trends associated with AEMT in this population have been unclear.

Objective

We aimed to clarify the trends in the incidence, disability‐adjusted life years (DALYs) and mortality rates of AEMT for children in the US from 2000 to 2019.

Methods

Data were retrieved from the Global Burden of Disease study 2019. We estimated age‐standardized incidence, DALYs and mortality rates of paediatric AEMT per 100,000 children in the US using a Bayesian meta‐regression model. We also analysed incidence, DALYs and mortality in different age groups, and employed Joinpoint regression models to assess the age‐ and sex‐specific trends.

Results

The number of deaths due to AEMT in children, the number of cases, and DALYs were 105.1, 551,076 and 145,555 in 2019, decreased by 37.5%, 6% and 28% from those in 2000, respectively. Age‐standardized mortality rates decreased across all age groups, while the incidence increased across all age groups with an average annual percentage change (AAPC) of 2.2% in those children <1 year and 4.5% in 5–9 years of age. The increases in DALYs over time was higher in children aged 1–4 years (AAPC: 0.51, 95% CI: 0.47, 0.62) and 5–9 years (AAPC: 0.33, 95% CI: 0.15, 0.50), with the 1–4 year age group being the highest.

Conclusion

The study reveals declining AEMT mortality but rising incidence and DALYs, emphasizing a disproportionate burden in <1, 1–4 and 5–9 years. To develop effective mitigation strategies, future research is warranted to identify the causes of increased AEMT in children, especially young males.
Evaluating the performance of Polylepis incana seeds: reassessing their potential for restoration and conservation of high Andean forests
Authors: Quispe‐Melgar Harold Rusbelth , Huayta‐Hinojosa L. David , Llacua‐Tineo Yashira Stefani , Ames‐Martínez Fressia N. , Lagones Poma Katherine L. , Ticse‐Otarola Ginette , Tomazello‐Filho Mario , Renison Daniel
Published: September 2024

The use of high‐quality seeds is essential for reforestation and ecosystem restoration; however, few Andean species have been assessed to determine factors influencing seed quality. Most Andean native tree species used for restoration are propagated from naturally regenerated seedlings or cuttings. We evaluated the seed quality (germination, viability, vigor, and physical characteristics) of a central Peruvian population of the keystone high Andean tree species Polylepis incana (quinual) in relation to the mother tree and microsite characteristics. Our analysis, using 12,912 seeds categorized by weight, included germination tests in incubator, tetrazolium tests, and vigor test (germination in nursery conditions). Results showed a mean germination rate of 30.9 ± 22.4%, with a significant proportion of damaged (38.7%), empty (19.1%), and non‐viable (12.7%) seeds. Heavier seeds exhibited the highest germination, while dasometric variables of the mother tree were not related to seed performance. However, solar incidence and slope negatively impacted germination. We conclude that seed quality may be higher than previously estimated, supporting the need to re‐evaluate and promote the use of seeds for propagating P. incana. Furthermore, since the characteristics of mother trees seem not to be relevant for this species and only solar incidence and terrain slope seem to negatively affect seed quality, we consider it important to change the paradigm from identifying individual seed trees to identifying seed forests. Conservation of natural forests as primary seed sources should be the foundation of future reforestation and restoration efforts in the high Andes.
Therapeutic potential of silkworm sericin in wound healing applications
Authors: Prakash Monika , Mathikere Naganna Chandraprabha , Radhakrishnan Vivek , Somayaji Prathik , Sabu Leah
Published: September 2024

Chronic wounds are characterised by an imbalance between pro and anti‐inflammatory signals, which result in permanent inflammation and delayed re‐epithelialization, consequently hindering wound healing. They are associated with bacterial infections, tissue hypoxia, local ischemia, reduced vascularization and MMP‐9 upregulation. The global prevalence of chronic wounds has been estimated at 40 million in the adult population, with an alarming annual growth rate of 6.6%, making it an increasingly significant clinical problem. Sericin is a natural hydrophilic protein obtained from the silkworm cocoon. Due to its biocompatibility, biodegradability, non‐immunogenicity and oxidation resistance, coupled with its excellent affinity for target biomolecules, it holds great potential in wound healing applications. The silk industry discards 50,000 tonnes of sericin annually, making it a readily available material. Sericin increases cell union sites and promotes cell proliferation in fibroblasts and keratinocytes, thanks to its cytoprotective and mitogenic effects. Additionally, it stimulates macrophages to release more therapeutic cytokines, thus improving vascularization. This review focuses on the biological properties of sericin that contribute towards enhanced wound healing process and its mechanism of interaction with important biological targets involved in wound healing. Emphasis is placed on diverse wound dressing products that are sericin based and the utilisation of nanotechnology to design sericin nanoparticles that aid in chronic wound management.
Properties of Central Regions of the Dark Matter Halos in the Model with a Bump in the Power Spectrum of Density Perturbations
Authors: Eroshenko Yu. N. , Lukash V. N. , Mikheeva E. V. , Pilipenko S. V. , Tkachev M. V.
Published: September 2024

A surprisingly large number of galaxies with masses of ~109–1010$${{M}_{ \odot }}$$ at redshifts of $$z \geqslant 9$$ are discovered with the James Webb Space Telescope. A possible explanation for the increase in the mass function can be the presence of a local maximum (bump) in the power spectrum of density perturbations on the corresponding scale. In this paper, it is shown that simultaneously with the growth of the mass function, galaxies from the bump region must have a higher density (compactness) compared to cosmological models without a bump. These more compact galaxies have been partially included in larger galaxies and have been subjected to tidal gravitational disruption. They have been less destructed than “ordinary” galaxies of the same mass, and some of them could survive to z = 0 and persist on the periphery of some galaxies. The formation and evolution of compact halos in a cube with a volume of (47 Mpc)3 with (1024)3 dark matter particles in the redshift range from 120 to 0 have been numerically simulated and observational implications of the presence of such galaxies in the current Universe have been discussed.
An examination of exercise intensity and its impact on the acute release of irisin across obesity status: a randomized controlled crossover trial
Authors: Rioux Brittany V. , Paudel Yadab , Thomson Amy M. , Peskett Logan E. , Sénéchal Martin
Published: September 2024

Limited data exist regarding the impact of exercise intensity on irisin release and its association with insulin sensitivity in individuals of differing obesity status. The objective of this study was to investigate the impact of exercise intensity on the acute release of irisin in healthy-weight individuals and individuals with obesity, and whether irisin release during acute exercise was associated with greater insulin sensitivity across obesity status. A randomized controlled crossover study was conducted on 26 non-overweight/obese (non-OW/OB) (BMI: 22.2 ± 1.5  kg/m2) and 26 overweight/obese (OW/OB) (BMI: 33.9 ± 6.5  kg/m2) adults who performed an acute bout of moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), and rest. Irisin was quantified via ELISA and western blotting, and insulin sensitivity (Si) was estimated using the Matsuda index. OW/OB displayed a significantly lower level of circulating irisin and protein expression compared to non-OW/OB ( p < 0.01). Insulin sensitivity was positively correlated with irisin release during MICT and HIIT in non-OW/OB (all p < 0.05), but not in OW/OB. Regarding irisin expression, non-OW/OB with high Si had a 2.03-fold ( p < 0.05) increase during HIIT, while OW/OB with high Si had only a 1.54-fold increase ( p < 0.05). These results suggest that irisin is released differently according to obesity status and varying exercise intensities. OW/OB individuals have a blunted irisin response to acute exercise and lower baseline irisin concentrations compared to non-OW/OB individuals. Although exercise stimulates irisin release in non-OW/OB individuals, only a greater exercise intensity stimulates irisin release in OW/OB individuals. These findings are clinically relevant, as irisin is associated with greater insulin sensitivity. This trial was registered at clinicaltrials.gov (NCT03514238).
Amplifying Research: The Potential for Podcasts to Boost Radiology Journal Article Exposure
Authors: Wang Mark , Le Thuy , Leswick David A.
Published: September 2024

Articles featured on the Radiology podcast had significantly higher exposure metrics, including downloads, citations, and Altmetric Attention Scores, compared with journal articles not featured on the podcast.
Performance of GPT-4 with Vision on Text- and Image-based ACR Diagnostic Radiology In-Training Examination Questions
Authors: Hayden Nolan , Gilbert Spencer , Poisson Laila M. , Griffith Brent , Klochko Chad
Published: September 2024

While OpenAI’s GPT-4 with vision demonstrated a level of competency in answering text-based radiology in-training examination questions, the model showed deficits in analyzing key radiologic images.
Highlights of the 2023 Amendments to the MQSA Implementing Regulations
Authors: Lerner David L.
Published: September 2024

The amendments to the Mammography Quality Standards Act regulations are effective on September 10, 2024, and affect many aspects of the program; the Food and Drug Administration offers multiple resources to help facilities understand and comply with the amended regulations.
Muscle protein catabolism and splanchnic arginine consumption drive arginine dysregulation during Pseudomonas aeruginosa-induced early acute sepsis in swine
Authors: Rice Sarah A. , Ten Have Gabriella A. M. , Engelen Marielle P. K. J. , Deutz Nicolaas E. P.
Published: September 2024

Our work highlights that arginine availability may be largely determined by muscle breakdown and hepatic extraction in early sepsis, while citrulline production appears maintained. Additionally, our work highlights a novel ANCOVA approach for transorgan analysis to control for inherent variation in transorgan data and increase statistical sensitivity.
Understanding Melasma: From Pathogenesis to Innovative Treatments
Authors: Zheng Hongjie , Pei Qing , Yao Min
Published: September 2024

Melasma is a common chronic acquired pigmentation disorder that is recognized as a type of photoaging disorder. Although the exact etiology and pathogenesis of melasma remain elusive, it is widely believed that it is triggered by multiple factors and involves multiple cells. Because of its impact on appearance and self‐confidence, melasma can affect the mental health and quality of life of patients. Various types of therapies have been used to treat melasma; however, the treatment of melasma remains challenging because of its eradication difficulty and almost constant relapses. Energy‐based and combination therapies have recently become a new trend with surprising therapeutic outcomes. This work provides an overview of the clinical characteristics, etiology, pathogenesis, histopathologic features, and management of melasma.
On the Assessment of the Chilean Solar Thermal Regulation Using a Modular Simulation Model Coupled to a Multiobjective Optimization Algorithm
Authors: Contreras Jorge , Kadoch Benjamin , Bustos Fabián
Published: September 2024

In Chile, the solar thermal regulation DS331, which utilizes a global modeling approach, governs the deployment of solar thermal systems (STSs) across highly variable climatic zones. This regulation’s one‐size‐fits‐all approach often misrepresents the solar potential and economic feasibility in different regions. To address these limitations, we introduce a refined modular energy model that incorporates a 1D multinode stratification technique for hot water storage. This model is associated with a multiobjective optimization process using the NSGA‐II algorithm, focusing on optimizing the solar collector area and storage volume to maximize solar fraction and life cycle savings (LCSs) across 20 major Chilean cities. Our results demonstrated that the optimized systems achieve solar fractions ranging from 0.92 to 1.00, significantly improving upon the current regulation’s performance, particularly in southern regions where solar radiation is lower. Notably, the optimized configurations suggested a potential reduction in collector areas by up to 20% and storage volumes by up to 15% compared to those recommended by DS331, while still exceeding the legal requirements for the solar fraction. This optimization made it possible to increase LCS by ~25%–30% across various scenarios, indicating a substantial improvement in cost‐effectiveness. Based on these findings, existing solar thermal regulations should be revised to take into account local climatic and consumption data. Such adjustments would ensure more accurate sizing of STS, enhanced economic viability, and greater incentive alignment for widespread adoption. This study underlines the critical role of detailed, location‐specific energy modeling in shaping effective energy policies and advancing the deployment of renewable technologies in diverse environmental contexts.
Effect of Smoking on Seminal Plasma Vitamin B6 in Fertile and Subfertile Men
Authors: Aljabali Shefa’ Muneer , Banihani Saleem Ali
Published: September 2024

Despite extensive documentation of the negative consequences of smoking on a wide range of diseases and disorders, the direct effect of smoking on seminal plasma vitamin B6 (vitB6) concentration is not addressed yet. Here, we attempted to examine the influence of smoking on the levels of seminal plasma vitB6 in fertile and subfertile males. One hundred and ninety‐five participants were categorized into two groups: fertile men (smokers (n = 32), nonsmokers (n = 43)) and subfertile men (smokers (n = 65), nonsmokers (n = 55)). According to the World Health Organization criteria, conventional semen analysis was performed for all subjects involved in the study. The concentration of vitB6 in semen samples was measured by high‐performance liquid chromatography tandem‐mass spectrometry. There was no significant difference in the mean seminal plasma concentrations of vitB6 in smokers versus nonsmokers in both fertile (p = 0.5096) and subfertile (p = 0.5224) groups. Besides, no significant correlations were observed between seminal plasma concentration of vitB6, duration of smoking, and men’s age in all tested groups. In conclusion, these findings elucidate that smoking has no significant impact on the levels of seminal plasma vitB6 in both fertile and subfertile men.
Supplementary Table S4 from Long-Term Risks of Cardiovascular Death among Older Patients with Major Hematological Malignancies: A Population-Based Cohort Study from SEER Database
Authors: Zhang Hanqing , He Minghao , Zhang Peng , Gao Yang , Ouyang Ling , He Xianjun , Han Na , Zhang Jinfeng , Guan Mengshan , Feng Yueqi , Li Yonghua
Published: September 2024

Supplementary Table S4. Characteristics of radiotherapy and Ann Arbor stage in older patients with lymphoma.
Supplementary Table S10 from Long-Term Risks of Cardiovascular Death among Older Patients with Major Hematological Malignancies: A Population-Based Cohort Study from SEER Database
Authors: Zhang Hanqing , He Minghao , Zhang Peng , Gao Yang , Ouyang Ling , He Xianjun , Han Na , Zhang Jinfeng , Guan Mengshan , Feng Yueqi , Li Yonghua
Published: September 2024

Supplementary Table S10. Cerebrovascular disease-related Standardized Mortality Ratios in older patient with different types of hematological malignancies based on years after diagnosis.
Supplementary Figure S3 from Long-Term Risks of Cardiovascular Death among Older Patients with Major Hematological Malignancies: A Population-Based Cohort Study from SEER Database
Authors: Zhang Hanqing , He Minghao , Zhang Peng , Gao Yang , Ouyang Ling , He Xianjun , Han Na , Zhang Jinfeng , Guan Mengshan , Feng Yueqi , Li Yonghua
Published: September 2024

Supplementary Figure S3. The distribution of causes of deaths among older patients with hematological malignancies (1975-1983). For each panel, we show the distribution based on different causes of death, the distribution of all four causes of deaths (a), the distribution of all causes of non-malignancies deaths (b), the distribution of all causes of CVD-related deaths (c). The time interval does not include the upper limit. Abbreviations: CVD, Cardiovascular Disease
Supplementary Figure S2 from Long-Term Risks of Cardiovascular Death among Older Patients with Major Hematological Malignancies: A Population-Based Cohort Study from SEER Database
Authors: Zhang Hanqing , He Minghao , Zhang Peng , Gao Yang , Ouyang Ling , He Xianjun , Han Na , Zhang Jinfeng , Guan Mengshan , Feng Yueqi , Li Yonghua
Published: September 2024

Supplementary Figure S2. The distribution of causes of deaths among older patients with hematological malignancies base on years after diagnosis. For each panel, we show the distribution based on different causes of death, the distribution of all causes of non-malignancies deaths (a), the distribution of all causes of CVD-related deaths (b). The time interval does not include the upper limit. Abbreviations: CVD, Cardiovascular Disease
Supplementary Figure S12 from Long-Term Risks of Cardiovascular Death among Older Patients with Major Hematological Malignancies: A Population-Based Cohort Study from SEER Database
Authors: Zhang Hanqing , He Minghao , Zhang Peng , Gao Yang , Ouyang Ling , He Xianjun , Han Na , Zhang Jinfeng , Guan Mengshan , Feng Yueqi , Li Yonghua
Published: September 2024

Supplementary Figure S12. The cumulative mortality among older patients with hematological malignancies based on different types of hematological malignancy (age at diagnosis: 85+). For each panel, we show the cumulative mortality curve for older patients among all 7 types of hematological malignancies: acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma. Abbreviations: CVD, Cardiovascular Disease
Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers
Authors: Zheng Yingye , Wagner Paul D. , Singal Amit G. , Hanash Samir M. , Srivastava Sudhir , Huang Ying , Zhao Ying-Qi , Chari Suresh T. , Marquez Guillermo , Etizioni Ruth , Marsh Tracey L. , Feng Ziding
Published: September 2024

Before implementing a biomarker in routine clinical care, it must demonstrate clinical utility by leading to clinical actions that positively affect patient-relevant outcomes. Randomly controlled early detection utility trials, especially those targeting mortality endpoint, are challenging due to their high costs and prolonged duration. Special design considerations are required to determine the clinical utility of early detection assays. This commentary reports on discussions among the National Cancer Institute’s Early Detection Research Network investigators, outlining the recommended process for carrying out single-organ biomarker-driven clinical utility studies. We present the early detection utility studies in the context of phased biomarker development. We describe aspects of the studies related to the features of biomarker tests, the clinical context of endpoints, the performance criteria for later phase evaluation, and study size. We discuss novel adaptive design approaches for improving the efficiency and practicality of clinical utility trials. We recommend using multiple strategies, including adopting real-world evidence, emulated trials, and mathematical modeling to circumvent the challenges in conducting early detection utility trials.
Lung Microbial and Host Genomic Signatures as Predictors of Prognosis in Early-Stage Adenocarcinoma
Authors: Tsay Jun-Chieh J. , Darawshy Fares , Wang Chan , Kwok Benjamin , Wong Kendrew K. , Wu Benjamin G. , Sulaiman Imran , Zhou Hua , Isaacs Bradley , Kugler Matthias C. , Sanchez Elizabeth , Bain Alexander , Li Yonghua , Schluger Rosemary , Lukovnikova Alena , Collazo Destiny , Kyeremateng Yaa , Pillai Ray , Chang Miao , Li Qingsheng , Vanguri Rami S. , Becker Anton S. , Moore William H. , Thurston George , Gordon Terry , Moreira Andre L. , Goparaju Chandra M. , Sterman Daniel H. , Tsirigos Aristotelis , Li Huilin , Segal Leopoldo N. , Pass Harvey I.
Published: September 2024

Background:

Risk of early-stage lung adenocarcinoma recurrence after surgical resection is significant, and the postrecurrence median survival is approximately 2 years. Currently, there are no commercially available biomarkers that predict recurrence. In this study, we investigated whether microbial and host genomic signatures in the lung can predict recurrence.

Methods:

In 91 patients with early-stage (stage IA/IB) lung adenocarcinoma with extensive follow-up, we used 16s rRNA gene sequencing and host RNA sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples.

Results:

Of 91 subjects, 23 had tumor recurrence over 5-year period. In tumor samples, lung adenocarcinoma recurrence was associated with enrichment in Dialister and Prevotella, whereas in unaffected lung samples, recurrence was associated with enrichment in Sphingomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with lung adenocarcinoma recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial–host features in the unaffected lung samples associated with recurrence, enrichment in Stenotrophomonas geniculata and Chryseobacterium was positively correlated with upregulation of IL2, IL3, IL17, EGFR, and HIF1 signaling pathways among the host transcriptome. In tumor samples, enrichment in Veillonellaceae (Dialister), Ruminococcaceae, Haemophilus influenzae, and Neisseria was positively correlated with upregulation of IL1, IL6, IL17, IFN, and tryptophan metabolism pathways.

Conclusions:

Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC = 0.83).

Impact:

This study suggests that lung adenocarcinoma recurrence is associated with distinct pathophysiologic mechanisms of microbial–host interactions in the unaffected lung rather than those present in the resected tumor.
Searching for the Scale-Able Weight Loss Intervention: Can One Size Fit All? Lessons to Be Learned from the EQUAL Trial
Authors: Moore Travis R. , Demark-Wahnefried Wendy
Published: September 2024

Overweight and obesity affect 71.2% of adults in the United States, with cancer survivors not far behind at 70.3%. Subgroups such as those diagnosed with acute lymphoblastic leukemia (ALL) face even greater challenges. The Exercise and Quality Diet after Leukemia (EQUAL) trial sought to address weight management issues among ALL survivors by implementing a remotely delivered weight loss intervention, leveraging the previously proven Practice-based Opportunities for Weight Reduction (POWER) program. Despite a strong foundation and design, the EQUAL trial yielded null results. Key differences in study populations and intervention contexts between the EQUAL and POWER trials, such as the lack of primary care physician involvement in EQUAL, contributed to these outcomes. EQUAL’s failure to meet its accrual target and poor adherence among participants highlighted challenges in engaging this unique population. Contrary to EQUAL’s conclusions, evidence from other studies supports the efficacy of remote interventions for weight loss among cancer survivors. The lack of qualitative assessment among ALL survivors and key integration to inform intervention adaptations undermined EQUAL’s impact. However, EQUAL’s impressive retention rate offers valuable insights. Lessons from EQUAL underscore the need for well-fitted, remotely delivered interventions and the importance of thoughtfully adapted and tailored approaches to specific survivor populations.

See related article by Fiedmann et al., p. 1158
Supplementary Figure S1 from Streamlined Intraoperative Brain Tumor Classification and Molecular Subtyping in Stereotactic Biopsies Using Stimulated Raman Histology and Deep Learning
Authors: Reinecke David , Ruess Daniel , Meissner Anna-Katharina , Fürtjes Gina , von Spreckelsen Niklas , Ion-Margineanu Adrian , Khalid Florian , Blau Tobias , Stehle Thomas , Al-Shugri Abdulkader , Büttner Reinhard , Goldbrunner Roland , Ruge Maximilian I. , Neuschmelting Volker
Published: September 2024

Supplementary Figure S1. Illustration of unprocessed sample processing and corresponding field of view (FOV) size selection.
Supplementary Table S2 from Maximizing Treatment Opportunities: Assessing Protocol Waivers’ Impact on Safety and Outcome in the Drug Rediscovery Protocol
Authors: van Berge Henegouwen Jade M. , Zeverijn Laurien J. , Geurts Birgit S. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , Huitema Alwin D.R. , de Vos Filip Y.F. , Grünberg Katrien , Bloemendal Haiko J. , Verheul Henk M.W. , Voest Emile E. , Gelderblom Hans
Published: September 2024

An overview of all reported serious adverse events in the study subgroup that received a waiver to participate in the trial
Supplementary Figure S8 from A Phase II Study of Potentiation of Pembrolizumab with Binimetinib and Bevacizumab in Refractory Microsatellite-Stable Colorectal Cancer
Authors: Lentz Robert W. , Friedrich Tyler J. , Blatchford Patrick J. , Jordan Kimberly R. , Pitts Todd M. , Robinson Hannah R. , Davis S. Lindsey , Kim Sunnie S. , Leal Alexis D. , Lee Mathew R. , Waring Meredith R.N. , Martin Anne C. , Dominguez Adrian T.A. , Bagby Stacey M. , Hartman Sarah J. , Eckhardt S. Gail , Messersmith Wells A. , Lieu Christopher H.
Published: September 2024

Supplementary Figure S8. Correlation of baseline immune cell populations with response to treatment in patients with and without liver metastases.
Supplementary Figure S6 from Multiplexed Spatial Profiling of Hodgkin Reed–Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma
Authors: Pourmaleki Maryam , Jones Caitlin J. , Mellinghoff Sabrina D. , Greenstein Brian D. , Kumar Priyadarshini , Foronda Miguel , Navarrete Daniel A. , Campos Carl , Roshal Mikhail , Schultz Nikolaus , Shah Sohrab P. , Schietinger Andrea , Socci Nicholas D. , Hollmann Travis J. , Dogan Ahmet , Mellinghoff Ingo K.
Published: September 2024

Supplementary Figure S6. EBV-positive tumors exhibit increased expression of VISTA.
Supplemental Figure 5 from Tumor-Agnostic Genomic and Clinical Analysis of BRAF Fusions Identifies Actionable Targets
Authors: Chen Monica F. , Yang Soo-Ryum , Tao Jessica J. , Desilets Antoine , Diamond Eli L. , Wilhelm Clare , Rosen Ezra , Gong Yixiao , Mullaney Kerry , Torrisi Jean , Young Robert J. , Somwar Romel , Yu Helena A. , Kris Mark G. , Riely Gregory J. , Arcila Maria E. , Ladanyi Marc , Donoghue Mark T.A. , Rosen Neal , Yaeger Rona , Drilon Alexander , Murciano-Goroff Yonina R. , Offin Michael
Published: September 2024

Supplemental Figure 5. Oncoprint for de novo BRAF fusions (≥10%) for most common histologies.
Supplementary Figure S1 from Multiplexed Spatial Profiling of Hodgkin Reed–Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma
Authors: Pourmaleki Maryam , Jones Caitlin J. , Mellinghoff Sabrina D. , Greenstein Brian D. , Kumar Priyadarshini , Foronda Miguel , Navarrete Daniel A. , Campos Carl , Roshal Mikhail , Schultz Nikolaus , Shah Sohrab P. , Schietinger Andrea , Socci Nicholas D. , Hollmann Travis J. , Dogan Ahmet , Mellinghoff Ingo K.
Published: September 2024

Supplementary Figure S1. Validation of mpIF antibody panel.
Supplementary Table S2 from An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials
Authors: Jank Paul , Karn Thomas , van Mackelenbergh Marion , Lindner Judith , Treue Denise , Huober Jens , Engels Knut , Solbach Christine , Diebold Kurt , Marmé Frederik , Müller Volkmar , Schneeweiss Andreas , Sinn Hans-Peter , Fehm Tanja , Schem Christian , Stickeler Elmar , Fasching Peter , Budczies Jan , Felder Bärbel , Nekljudova Valentina , Holtschmidt Johannes , Untch Michael , Denkert Carsten , Loibl Sibylle
Published: September 2024

pCR rates in molecular subgroups
Data from Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers
Authors: French Jena D. , Haugen Bryan R. , Worden Francis P. , Bowles Daniel W. , Gianoukakis Andrew G. , Konda Bhavana , Dadu Ramona , Sherman Eric J. , McCue Shaylene , Foster Nathan R. , Nikiforov Yuri E. , Farias Ticiana D.J. , Norman Paul J. , Wirth Lori J.
Published: September 2024

AbstractPurpose:
Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients.
Patients and Methods:
We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days.
Results:
In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0–17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1.
Conclusions:
Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.
Data from Multiplexed Spatial Profiling of Hodgkin Reed–Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma
Authors: Pourmaleki Maryam , Jones Caitlin J. , Mellinghoff Sabrina D. , Greenstein Brian D. , Kumar Priyadarshini , Foronda Miguel , Navarrete Daniel A. , Campos Carl , Roshal Mikhail , Schultz Nikolaus , Shah Sohrab P. , Schietinger Andrea , Socci Nicholas D. , Hollmann Travis J. , Dogan Ahmet , Mellinghoff Ingo K.
Published: September 2024

AbstractPurpose:
Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1%–5%) of the malignant Hodgkin Reed–Sternberg (HRS) cells within a network of nonmalignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown.
Experimental Design:
We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein–Barr virus (EBV)-positive and EBV-negative cHL tumors.
Results:
We show that MHC-I expression on HRS cells is associated with immune-inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T-cell–excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T-cell–high neighborhoods harboring HRS cells with augmented proliferative capacity.
Conclusions:
Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.
Data from Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors
Authors: Choi Yoonha , Dharia Neekesh V. , Jun Tomi , Chang Julie , Royer-Joo Stephanie , Yau Kenneth K. , Assaf Zoe J. , Aimi Junko , Sivakumar Smruthy , Montesion Meagan , Sacher Adrian , LoRusso Patricia , Desai Jayesh , Schutzman Jennifer L. , Shi Zhen
Published: September 2024

AbstractPurpose:
To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study.
Experimental Design:
Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1).
Results:
KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non–small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction.
Conclusions:
Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.
A Phase II Study of Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer
Authors: Giordano Antonio , Kumthekar Priya U. , Jin Qingchun , Binboga Kurt Busem , Ren Siyang , Li Tianyu , Leone Jose Pablo , Mittendorf Elizabeth A. , Pereslete Alyssa M. , Sharp Laura , Davis Raechel , DiLullo Molly , Tayob Nabihah , Mayer Erica L. , Winer Eric P. , Tolaney Sara M. , Lin Nancy U.
Published: September 2024

Purpose:

Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response.

Patients and Methods:

This was a single-arm, multicenter, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1,200 mg i.v. every 3 weeks, pertuzumab (loading dosage 840 mg i.v., then 420 mg i.v. every 3 weeks), and high-dose trastuzumab (6 mg/kg i.v. weekly for 24 weeks, then 6 mg/kg i.v. every 3 weeks). The primary endpoint was CNS overall response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria. Key secondary endpoints included CBR, overall survival, and safety and tolerability of the combination.

Results:

Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS overall response rate of 10.5% (90% confidence interval, 1.9%–29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%).

Conclusions:

The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.