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Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p

Purpose: To investigate in vivo(1)H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes.Methods and Materials: Volume-localized lactate-edited (1)H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO(2)) was obtained in the same lymph node before MRS. Patients were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO(2), nodal response, and locoregional control.Results: The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO(2) (mean, 0.46 +/- 0.10 for hypoxic nodes [pO(2) < or =10 mm Hg, n = 15] vs. 0.36 +/- 0.07 for nonhypoxic nodes [pO(2) >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO(2) (mean, 2.74 +/- 0.34 for hypoxic nodes vs. 1.78 +/- 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates.Conclusions: The lactate SI did not correlate with tumor pO(2), treatment response, or locoregional control. Additional research is needed to refine this technique. [ABSTRACT FROM AUTHOR]

Background: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.Methods: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.Results: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.Conclusions: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose. [ABSTRACT FROM AUTHOR]

Background: Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab., Methods: NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III-IVB p16-negative HNSCC or unfavourable stage I-III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m 2 1 week before radiotherapy then 250 mg/m 2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment., Findings: Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64-77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9-3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5-59·8) in the durvalumab group versus 63·7% (51·3-76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84-2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3-4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group)., Interpretation: Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population., Funding: US National Cancer Institute and AstraZeneca., Competing Interests: Declaration of interests MJA declares grants or contracts from the National Institutes of Health (NIH; R21 for phase 1 trial DEHART), receipt of equipment, materials, drugs, medical writing, gifts, or other services from Genentech for drug only support for NIH R21. JEB declares clinical trial grants from Aveo, Celldex, CUE, Genentech, and Moderna, and consulting fees from Bluedot Bio and Exelixis. ND declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca. CH declares participation on a medical advisory board for EMD Serono, and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid as co-chair of the Young Investigators Committee of the Head and Neck Cancer International Group. RCJ declares royalties or license from Elsevier for a textbook authorship. Q-TL declares a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid as Radiation Therapy Oncology group chair for NRG Oncology. LKM declares grants or contracts from AstraZeneca and Merck to their institution, consulting fees from Pfizer, and payment for expert testimony from Arnold & Porter. HSP declares grants or contracts from RefleXion and Merck to their institution, consulting fees from AstraZeneca and RefleXion, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb and G1 Therapeutics, and participation on a data safety monitoring board or advisory board at AstraZeneca and Galera. SP declares grants or contracts from Merck, Bristol Myers Squibb, Pfizer, Actuate, Vyriad, Nanobiotix, Seattle Genetics, AstraZeneca, Molecular Templates, and Sorrento to their institution, consulting fees from Bristol Myers Squibb to their institution, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alkermes to their institution. CPR declares grants or contracts from AstraZeneca, Ayala, BMS, Cue Biopharma, Merck, Prelude, Sanofi Aventis, and Seagen to their institution, consulting fees from Vaccitech and Adaptimmune, and participation on a data safety monitoring board or advisory board at Pionyr Therapeutics. AGS declares grants or contracts from Merck, Bicara, AstraZeneca, Genentech/Roche, ALX Oncology, Regeneron, and Infinity Pharmaceuticals to their institution, consulting fees from Bicara, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from i3Health. VT declares grants or contracts from NIH and Veteran's Administration, support for attending meetings or travel from the American Society for Radiation Oncology and the American Board of Radiology, and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Cardiff Oncology. PAT-S declares support for the current manuscript from NRG Oncology Statistics and Data Management Center grant from NCI. TW-D declares grants or contracts from Bristol Myers Squibb, Merck, Janssen, AstraZeneca/Medimmune, and Tesaro/GSK, and participation on a data safety monitoring board or advisory board at Merck. SSY declares grants or contracts from Bristol Myers Squibb and EMD Serono to their institution, honoraria for editorship from Elsevier, and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid at ASTRO for editorship. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Agriculture is vital for global food security, and irrigation is essential for improving crop yields. However, irrigation can pose challenges such as mineral scarcity and salt accumulation in the soil, which negatively impact plant growth and crop productivity. While numerous studies have focused on enhancing plant tolerance to high salinity, research targeting various ecotypes of Arabidopsis thaliana has been relatively limited. In this study, we aimed to identify salt-tolerant ecotypes among the diverse wild types of Arabidopsis thaliana and elucidate their characteristics at the molecular level. As a result, we found that Catania-1 (Ct-1), one of the ecotypes of Arabidopsis, exhibits greater salt tolerance compared to Col-0. Specifically, Ct-1 exhibited less damage from reactive oxygen species (ROS) than Col-0, despite not accumulating antioxidants like anthocyanins. Additionally, Ct-1 accumulated more potassium ions (K + ) in its shoots and roots than Col-0 under high salinity, which is crucial for water balance and preventing dehydration. In contrast, Ct-1 plants were observed to accumulate slightly lower levels of Na + than Col-0 in both root and shoot tissues, regardless of salt treatment. These findings suggest that Ct-1 plants achieve high salinity resistance not by extruding more Na + than Col-0, but rather by absorbing more K + or releasing less K + . Ct-1 exhibited higher nitrate (NO 3 - ) levels than Col-0 under high salinity conditions, which is associated with enhanced retention of K + ions. Additionally, genes involved in NO 3 - transport and uptake, such as NRT1.5 and NPF2.3, showed higher transcript levels in Ct-1 compared to Col-0 when exposed to high salinity. However, Ct-1 did not demonstrate significantly greater resistance to osmotic stress compared to Col-0. These findings suggest that enhancing plant tolerance to salt stress could involve targeting the cellular processes responsible for regulating the transport of NO 3 - and K + . Overall, our study sheds light on the mechanisms of plant salinity tolerance, emphasizing the importance of K + and NO 3 - transport in crop improvement and food security in regions facing salinity stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSC gal ) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSC gal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSC gal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (Tert High ) cell population located in the ductal region of the adult SMG. These Tert High cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. Tert High cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in Tert High cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of Tert High cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy., (© 2024 Guan et al.; Published by Cold Spring Harbor Laboratory Press.)

Three main areas of research revolve around extracellular vesicles (EVs): their use as early detection diagnostics for cancer prevention, engineering of EVs or other enveloped viral-like particles for therapeutic purposes and to understand how EVs impact biological processes. When investigating the biology of EVs, it is important to consider strategies able to track and alter EVs directly in vivo , as they are released by donor cells. This can be achieved by suitable engineering of EV donor cells, either before implantation or directly in vivo. Here, we make a case for the study of native EVs, that is, EVs released by cells living within a tissue. Novel genetic approaches to detect intercellular communications mediated by native EVs and profile recipient cells are discussed. The use of Rab35 dominant negative mutant is proposed for functional in vivo studies on the roles of native EVs. Ultimately, investigations on native EVs will tremendously advance our understanding of EV biology and open novel opportunities for therapy and prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nambiar, Le and Pucci.)

Radiation therapy (RT) is one of the most effective treatments for cancer, and its success relies on the accurate delineation of targets. However, target delineation is a comprehensive medical decision that currently relies purely on manual processes by human experts. Manual delineation is time-consuming, laborious, and subject to interobserver variations. Although the advancements in artificial intelligence (AI) techniques have significantly enhanced the auto-contouring of normal tissues, accurate delineation of RT target volumes remains a challenge. In this study, we propose a visual language model-based RT target volume auto-delineation network termed Radformer. The Radformer utilizes a hierarchical vision transformer as the backbone and incorporates large language models to extract text-rich features from clinical data. We introduce a visual language attention module (VLAM) for integrating visual and linguistic features for language-aware visual encoding (LAVE). The Radformer has been evaluated on a dataset comprising 2985 patients with head-and-neck cancer who underwent RT. Metrics, including the Dice similarity coefficient (DSC), intersection over union (IOU), and 95th percentile Hausdorff distance (HD95), were used to evaluate the performance of the model quantitatively. Our results demonstrate that the Radformer has superior segmentation performance compared to other state-of-the-art models, validating its potential for adoption in RT practice.

Background: Screening with anti-Epstein-Barr virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China., Methods: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women aged 30-69). Seropositive subjects were rescreened annually for 5 years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial subcohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system., Results: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (¥42,366/life-year, 0.52 GDP per capita). Screening for 5 to 15 years between ages 35 and 59 years met a willingness-to-pay threshold of 1.5 GDP/quality-adjusted life-years in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One-lifetime screen could reduce NPC mortality by approximately 20%., Conclusions: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region., Impact: These findings support population-based screening in southern China by defining the target population, cost-effectiveness, and optimized screening approach., (©2024 American Association for Cancer Research.)

Radiotherapy treatment planning is a time-consuming and potentially subjective process that requires the iterative adjustment of model parameters to balance multiple conflicting objectives. Recent advancements in large foundation models offer promising avenues for addressing the challenges in planning and clinical decision-making. This study introduces GPT-RadPlan, a fully automated treatment planning framework that harnesses prior radiation oncology knowledge encoded in multi-modal large language models, such as GPT-4Vision (GPT-4V) from OpenAI. GPT-RadPlan is made aware of planning protocols as context and acts as an expert human planner, capable of guiding a treatment planning process. Via in-context learning, we incorporate clinical protocols for various disease sites as prompts to enable GPT-4V to acquire treatment planning domain knowledge. The resulting GPT-RadPlan agent is integrated into our in-house inverse treatment planning system through an API. The efficacy of the automated planning system is showcased using multiple prostate and head & neck cancer cases, where we compared GPT-RadPlan results to clinical plans. In all cases, GPT-RadPlan either outperformed or matched the clinical plans, demonstrating superior target coverage and organ-at-risk sparing. Consistently satisfying the dosimetric objectives in the clinical protocol, GPT-RadPlan represents the first multimodal large language model agent that mimics the behaviors of human planners in radiation oncology clinics, achieving remarkable results in automating the treatment planning process without the need for additional training.

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

Enzymatic hydrolysis of edible bird's nest (EBN) has attracted great interest in both scientific and commercial fields due to the enhancement of solubility and nutraceutical values. The present study attempted to investigate the hydrolysis of EBN with papaya ( Carica papaya L.), pineapple ( Ananas comosus (L.) Merr.), and cantaloupe ( Cucumis melo L.) juices as well as two commercial enzymes papain and bromelain. Our analysis revealed that EBN hydrolysis with pineapple juice and bromelain produced a degree of hydrolysis (DH) value of approximately 27 % while it was about 25 % for the hydrolysis with cantaloupe juice and 22 % for the hydrolysis with papaya juice and papain after 4 h of treatment. When EBN was digested by fruit juices and enzymes, the protein solubility and free sialic acid content were increased and the highest values were achieved for EBN hydrolysis with pineapple juice and bromelain (estimately 11 mg/mL of soluble protein and 18 g/kg of free sialic acid). The ABTS • + -scavenging, • OH-scavenging, and anti-tyrosinase capacities were higher in the EBN hydrolysates by papaya juice (IC 50 of 0.034, 0.108, and 0.419 mg/mL, respectively), pineapple juice (IC 50 of 0.025, 0.045, and 0.190 mg/mL, respectively), and cantaloupe juice (IC 50 of 0.031 mg/mL, 0.056, and 0.339 mg/mL, respectively) than in the hydrolysates by unhydrolyzed EBN (IC 50 of 0.094, 0.366, and 1.611 mg/mL, respectively). An improvement in ABTS • + -scavenging, • OH-scavenging, and anti-tyrosinase abilities was also observed for the hydrolysates by papain (IC 50 of 0.041, 0.129, and 0.417 mg/mL, respectively) and bromelain (IC 50 of 0.025, 0.069, and 0.336 mg/mL, respectively) but in a lesser extent as compared to the hydrolysates by respective papaya and pineapple juices. Noticeably, the EBN hydrolysates by fruit juices remarkably enhanced the wound closure in human fibroblasts by about 1.4-1.8 times after 24 h of treatment whereas this property was insignificant in the hydrolysates by enzymes. As papaya, pineapple, and cantaloupe juices are easily obtainable and have pleasant flavors, our results provide a possible method to hydrolyze EBN and apply the resultant hydrolysates in functional food products., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Recruiting prospective physicians to radiation oncology can be challenging, because of limited familiarity with the field. The Assistant Clinical Research Coordinator (ACRC) program can help provide trainees early exposure to radiation oncology., Methods and Materials: The ACRC program involves hiring a college graduate to provide administrative and research support for faculty members. The program was developed with our institution's clinical trials office, which provided guidance on regulatory compliance and training. A structured selection process identifies top candidates, and a rigorous onboarding process ensures smooth transitions between ACRCs. We report characteristics and outcomes of ACRC employees and surveyed them to assess their program experience using a Likert scale., Results: From 2005 to 2023, the ACRC program paired 73 ACRCs with faculty. Most faculty (68%) are currently supported by ACRCs. In 2023, 113 applications were received for 4 positions. ACRCs have contributed to research publications (293 as coauthors and 43 as first authors) and taken on leadership roles in the department. Most program alumni have attended medical school (34 of 64 program graduates; 53%). Eight have chosen to specialize in radiation oncology (13%; 2 applying into radiation oncology, 1 in residency, and 5 attendings). Of the 25% of alumni who responded to our survey, 77% responded that the mentorship provided by the ACRC program was very or extremely effective in guiding their academic development. All respondents rated the research opportunities as good or excellent, and 77% rated the clinical experience opportunities as good or excellent. Most (77%) reported that the ACRC program had substantial or significant influence on their choice of career path., Conclusions: The ACRC program provides an opportunity to address recruitment challenges in radiation oncology by offering early exposure to the field, clinical research skills, and mentorship. With the strong interest in our job posting this year, there is potential to expand this program to other institutions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

We demonstrate magnetic droplet soliton pairs in all-perpendicular spin-torque nano-oscillators (STNOs), where one droplet resides in the STNO free layer (FL) and the other in the reference layer (RL). Typically, theoretical, numerical, and experimental droplet studies have focused on the FL, with any additional dynamics in the RL entirely ignored. Here we show that there is not only significant magnetodynamics in the RL, but the RL itself can host a droplet driven by, and coexisting with, the FL droplet. Both single droplets and pairs are observed experimentally as stepwise changes and sharp peaks in the dc and differential resistance, respectively. While the single FL droplet is highly stable, the coexistence state exhibits high-power broadband microwave noise. Furthermore, micromagnetic simulations reveal that the pair dynamics display periodic, quasi-periodic, and chaotic signatures controlled by applied field and current. The strongly interacting and closely spaced droplet pair offers a unique platform for fundamental studies of highly non-linear soliton pair dynamics., (© 2024. The Author(s).)

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy., Methods: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r 2 greater than 0·7 was used as criteria for clinically relevant surrogacy., Findings: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r 2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r 2 0·83), and progression-free survival (Kendall's τ 0·88 and r 2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r 2 0·88), distant metastasis-free survival (r 2 0·96), and progression-free survival (r 2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival., Interpretation: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints., Funding: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan., Competing Interests: Declaration of interests LAG reports grant funding from the PROTEUS Consortium. JAB reports royalties or licenses from Bristol Myers Squibb, Eli Lilly, and Merck Serono; consulting fees from Cel-Sci, Merck Serano, and ICON; payment for lectures or presentations from Bristol Myers Squibb, Eli Lilly, Merck Serano, and Cel-Sci; and support for attending meetings or travel from Bristol Myers Squibb, Eli Lilly, and Merck Serono. MLG reports research funding from Genocea Biosciences, Bristol Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus, LaRoche, NRG Oncology, and the University of Cincinnati; consulting fees from iTeos Therapeutics, Istari Oncology, LLX Solutions, OncLive Intellisphere, Seagen, Sensei Biotherapeutics, Kura Oncology, Coherus Biosciences, Mirati Therapeutics, BioNtech AG, Sensei Biotherapeutics, Caladrius Biosciences, Bristol Myers Squibb, Bicara Therapeutics, Bayer Healthcare Pharmaceutics, Genocea Biosciences, Shattuck Labs, EMD Serono, Debiopharm, Merck & Co, Ipsen Biopharmaceuticals, Gilead Sciences, Nektar Therapeutics, Eisai Medical Research, Roche, Roche Diagnostics, NewLink Genetics, Aspyrian Therapeutics, Amgen, TRM Oncology, AstraZeneca Pharmaceuticals, Celgene, and Exelixis; payment from OncLive and Roche; and support for meetings or travel for presentations from the American Association for Cancer Research, the American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer. SK reports research funding from Merck, Bristol Myers Squibb, Castle Biosciences, and Regeneron; consulting fees from Merck, Bristol Myers Squibb, Regeneron, and Galera Therapeutics; and honorarium from Varian Medical Systems. Q-TL reports a leadership role as RTOG Group Chair for NRG Oncology and support from RTOG Foundation for attending meetings and travel. MM reports clinical trial drug support from Bristol Myers Squbb, and grant funding from the PROTEUS Consortium and Livestrong Foundation, advistory board of Adaptimmune. DLM reports a grant from the National Cancer Institute (3R01CA262388-02S1 NCI Diversity Supplement Award). EM reports a University of Michigan M-Cubed Grant (P30CA046592). JAR reports non-financial interests National Comprehensive Cancer Network Thyroid Cancer Panel and American Thyroid Association Guidelines Task Force. DIR reports payments from Merck to the Scientific Advisory Board for presentations. MJS reports consulting fees from Innovative Analytics. WAS reports a research grant from Georgia Research Alliance. PT-S reports NRG Oncology SDMC Grant from the National Cancer Institute (NCI). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Parabens (p-hydroxybenzoic acid esters) commonly used preservatives (in cosmetics, pharmaceuticals, and foods) can pose potential effects on environmental health. In this study, seven parabens were quantified in marine fish samples using an ultra-high performance liquid chromatography triple quadrupole mass spectrometer (UHPLC-MS/MS) system. Parabens in the fish samples were extracted and purified by a rapid, simple, and effective procedure comprising sample homogenization with solvent, solid-phase extraction clean-up, and solvent evaporation. Results demonstrated that the recoveries of seven compounds (with relative standard deviation < 15%) were 88-103% in matrix-spike samples and 86-105% in surrogate standards. The method detection limits and method quantification limits of seven parabens were 0.015-0.030 and 0.045-0.090 ng/g-ww (wet weight), respectively. The optimized method was applied to measure the concentration of parabens in the 37 marine fish samples collected from Vietnam coastal waters. The concentration ranges of seven parabens found in round scad and greater lizardfish samples were 6.82-25.3 ng/g ww and 6.21-17.2 ng/g-ww, respectively. Among parabens, methylparaben accounted for the highest contribution in both fish species (43.2 and 44.9%, respectively). Based on the measured concentrations of parabens in marine fish samples, the estimated daily intake was calculated for children and adults with the corresponding values of 0.0477 µg/kg/day and 0.0119 µg/kg/day, respectively. However, the presence of parabens in Vietnamese marine fish may not pose a significant risk to human health., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Whereas extracellular vesicles (EVs) have been engineered for cargo loading, innovative strategies for it can still be developed. Here, we describe domain 4 (D4), a cholesterol-binding domain derived from perfringolysin O, as a viable candidate for EV cargo loading. D4 and its mutants localized to the plasma membrane and the membranes of different vesicular structures in the cytoplasm, and facilitate the transport of proteins of interest (POIs) into EVs. D4-EVs were internalized by recipient cells analogous to EVs engineered with CD9. Intracellular cargo discharge from D4-EVs was successfully detected with the assistance of vesicular stomatitis virus glycoprotein. This study presents a novel strategy for recruiting POIs into EVs via a lipid-binding domain that ensures content release in recipient cells., (© 2024 Federation of European Biochemical Societies.)

This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Copy number variation sequencing (CNV-seq) is a powerful tool to discover structural genomic variation, but limitations associated with its retrospective study design and inadequate diversity of participants can be impractical for clinical application. Aim: This study aims to use CNV-seq to assess chromosomal aberrations in pregnant Vietnamese women. Materials & methods: A large-scale study was conducted on 3776 pregnant Vietnamese women with abnormal ultrasound findings. Results: Chromosomal aberrations were found in 448 (11.86%) women. Of these, 274 (7.26%) had chromosomal aneuploidies and 174 (4.61%) carried pathogenic/likely pathogenic CNVs. Correlations were established between chromosomal aberrations and various phenotypic markers. Conclusion: This comprehensive clinical study illuminates the pivotal role of CNV-seq in prenatal diagnosis for pregnancies featuring fetal ultrasound anomalies.

Background: A single institution retrospective study suggested that head and neck squamous cell cancer (HNSCC) patients receiving radiotherapy (RT) during "dark" season (fall/winter) may have better outcomes than those treated during "light" season (spring/summer), possibly secondary to seasonal variations in cell cycle progression. We investigated the impact of season of RT in two large, multi-institutional, prospective datasets of randomized trials., Methods: Individual patient data from the MACH-NC and MARCH meta-analyses were analyzed. Dark season was defined as mid-radiotherapy date during fall or winter and light the reverse, using equinoxes to separate the two periods. Primary endpoint was progression-free survival (PFS) and secondary endpoint was locoregional failure (LRF). The effect of season was estimated with a Cox model stratified by trial and adjusted on sex, tumor site, stage, and treatment. Planned sensitivity analyses were performed on patients treated around solstices, who received "complete radiotherapy", patients treated with concomitant radio-chemotherapy and on trials performed in Northern countries., Results: 11320 patients from 33 trials of MARCH and 6276 patients from 29 trials of MACH-NC were included. RT during dark season had no benefit on PFS in the MARCH (hazard ratio[HR]: 1.01 [95%CI 0.97;1.05],p=0.72) or MACH-NC dataset (HR:1.00 [95%CI 0.94;1.06],p=1.0. No difference in LRF was observed in the MARCH (HR:1.00 [95%CI 0.94;1.06,p=0.95) or MACH-NC dataset (HR:0.99 [95%CI 0.91; 1.07],p=0.77). Sensitivity analyses showed similar results., Conclusion: Season of RT had no impact on PFS or LRF in two large databases of HNSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

The effect of annealing temperature and capping ligands on the electron mobility and electronic structure of indium oxide (In 2 O 3 ) nanocrystals (NCs) was investigated using oleic acid (OA), benzoic acid (BA), and 4-aminobenzoic acid (4ABA). The NCs were deposited on SiO 2 /Si wafers for electron mobility measurements using a field effect transistor device, and the annealing temperature ( T Ann ) was varied from 150 to 350 °C. At T Ann = 200 °C, the electron mobility of the BA-capped In 2 O 3 NC thin film was greater than that of 4ABA-capped In 2 O 3 NCs, while the opposite trend was observed at T Ann = 250 °C. This difference can be attributed, at the lower annealing temperature, to the π-π interaction in the BA-capped In 2 O 3 NC thin film, which is hindered in the ABA-capped In 2 O 3 NC thin film owing to its -NH 2 group. At higher annealing temperature, NN bond formation in the ABA-capped In 2 O 3 NC thin film confirmed by Raman spectroscopy plays a key role even after significant thermal decomposition of the ligands in the In 2 O 3 NC thin films. At T Ann = 250 °C, the reorganization energy of BA- or 4ABA-capped In 2 O 3 NCs estimated in the framework of Marcus theory was very similar to each other, indicating that the ligands decompose almost completely, as confirmed by Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA). The electronic structure was studied by energy-resolved electrochemical impedance spectroscopy (ER-EIS) after annealing the NCs on ITO electrodes at T Ann = 150 °C, 200 °C, or 250 °C. The valence band peak was observed near -6.8 eV for the BA- or 4ABA-capped In 2 O 3 NC films at T Ann =150 °C or 200 °C, but not at T Ann =250 °C. However, for the OA-capped In 2 O 3 NCs, the peak near -6.8 eV was observed for all annealing conditions. Considering the exclusive perseverance of the carboxylate group in the OA-capped In 2 O 3 NCs even at T Ann = 250 °C, as confirmed by FT-IR and TGA, one attributes the peak at -6.8 eV to an electronic state formed by the electronic interaction between the In 2 O 3 NC and the carboxylate groups.

Chronic Kidney Disease (CKD) which involves gradual loss of kidney function is characterized by low levels of a glycoprotein called Erythropoietin (EPO) that leads to red blood cell  deficiency and anemia. Recombinant human EPO (rhEPO) injections that are administered intravenously or subcutaneously is the current gold standard for treating CKD. The rhEPO injections have very short half-lives and thus demands frequent administration with a risk of high endogenous EPO levels leading to severe side effects that could prove fatal. To this effect, this work provides a novel approach of using lamellar inorganic solids with a brucite-like structure for controlling the release of protein therapeutics such as rhEPO in injectable hydrogels. The nanoengineered injectable system was formulated by incorporating two-dimensional layered double hydroxide (LDH) clay materials with a high surface area into alginate hydrogels for sustained delivery. The inclusion of LDH in the hydrogel network not only improved the mechanical properties of the hydrogels (5-30 times that of alginate hydrogel) but also exhibited a high binding affinity to proteins without altering their bioactivity and conformation. Furthermore, the nanoengineered injectable hydrogels (INHs) demonstrated quick gelation, injectability, and excellent adhesion properties on human skin. The in vitro release test of EPO from conventional alginate hydrogels (Alg-Gel) showed 86% EPO release within 108 h while INHs showed greater control over the initial burst and released only 24% of EPO in the same incubation time. INH-based ink was successfully used for 3D printing, resulting in scaffolds with good shape fidelity and stability in cell culture media. Controlled release of EPO from INHs facilitated superior angiogenic potential in ovo (chick chorioallantoic membrane) compared to Alg-Gel. When subcutaneously implanted in albino mice, the INHs formed a stable gel in vivo without inducing any adverse effects. The results suggest that the proposed INHs in this study can be utilized as a minimally invasive injectable platform or as 3D printed patches for the delivery of protein therapeutics to facilitate tissue regeneration., (© 2023. The Author(s).)

Defining the loss function is an important part of neural network design and critically determines the success of deep learning modeling. A significant shortcoming of the conventional loss functions is that they weight all regions in the input image volume equally, despite the fact that the system is known to be heterogeneous (i.e., some regions can achieve high prediction performance more easily than others). Here, we introduce a region-specific loss to lift the implicit assumption of homogeneous weighting for better learning. We divide the entire volume into multiple sub-regions, each with an individualized loss constructed for optimal local performance. Effectively, this scheme imposes higher weightings on the sub-regions that are more difficult to segment, and vice versa. Furthermore, the regional false positive and false negative errors are computed for each input image during a training step and the regional penalty is adjusted accordingly to enhance the overall accuracy of the prediction. Using different public and in-house medical image datasets, we demonstrate that the proposed regionally adaptive loss paradigm outperforms conventional methods in the multi-organ segmentations, without any modification to the neural network architecture or additional data preparation.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC., Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS)., Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020., Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo)., Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS., Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84)., Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis., Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Background: Noninvasive prenatal tests for monogenic diseases (NIPT-SGG) have recently been reported as helpful in early-stage antenatal screening. Our study describes the clinical and genetic features of cases identified by NIPT-SGG. Materials & methods: In a cohort pregnancy with abnormal sonograms, affected cases were confirmed by invasive diagnostic tests concurrently, with NIPT-SGG targeting 25 common dominant single-gene diseases. Results: A total of 13 single-gene fetuses were confirmed, including Noonan and Costello syndromes, thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta and Apert syndrome. Two novel variants seen were tuberous sclerosis complex ( TSC2 c.4154G>A) and Alagille syndrome ( JAG1 c.3452del). Conclusion: NIPT-SGG and standard tests agree on the results for 13 fetuses with monogenic disorders. This panel method of screening can benefit high-risk Vietnamese pregnancies, but further research is encouraged to expand on the causative gene panel.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy., Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control., Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3)., Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3., Main Outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up., Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects)., Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials., Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Background: Few studies have addressed relationships between health literacy (HL) and nutritional awareness in preconception/pregnancy populations, especially within Asia. We explored the rationale for nutrition-related education and/or HL interventions to improve nutritional intake among preconception/pregnant women., Methods: A cross-sectional questionnaire-based real-world study was conducted among 100 preconception and 200 pregnant women in Vietnam in January/February 2022. The questionnaire included a validated screening tool for HL (Newest Vital Sign [NVS]), and questions on preconception/pregnancy-related nutritional knowledge and behavior, prenatal supplementation, sources of nutritional advice., Results: Most respondents (62%) had limited HL and only 5% had adequate HL. Respondents with limited HL (NVS 0-1) showed less awareness of benefits of healthy eating before/during pregnancy, such as reduction in risk of birth defects. Most (94%) considered prenatal supplements beneficial, yet 64% were not convinced of supplement safety. The limited HL group reported the lowest use of supplements, including multivitamins, iron, and folic acid/folate., Conclusion: The prevalence of limited HL and the low awareness of preconception/pregnancy-related nutrition suggest an urgent need to invest in nutrition-specific education and improving HL in maternal populations. This will help support adequate maternal nutrition and appropriate micronutrient supplementation before conception and throughout the "first 1000 days" of life., Competing Interests: The authors declare no conflict of interest., (© Quang Thanh Le et al., 2023; Published by Mary Ann Liebert, Inc.)

The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers., Significance: Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression., (©2023 American Association for Cancer Research.)