bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long term results of a randomized phase III study of nimotuzumab in combination with concurrent radiotherapy and cisplatin versus radiotherapy and cisplatin alone, in locally advanced squamous cell carcinoma of the head and neck.
Authors: Patil Vijay Maruti , Noronha Vanita , Menon Nandini Sharrel , Shah Minit Jalan , Ghosh Sarbani Laskar , Budrukkar Ashwini , Swain Monali , Balaji Arun , Chaukar Devendra , Pai Prathamesh S , Chaturvedi Pankaj , Prabhash Kumar 
Published: June 2024

LBA6092 Background: The addition of nimotuzumab to weekly cisplatin as a radiosensitizer had improved progression-free survival (PFS) in a phase 3 study in locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, whether it leads to an improvement in long-term OS is unknown. Hence this analysis was performed to evaluate the efficacy (in terms of OS) and late-term adverse events of the addition of nimotuzumab to concurrent chemoradiation in LA HNSCC. Methods: This was an open-label, investigator-initiated, phase 3 randomized trial conducted from 2012 - 2018. 536 adult patients with LA HNSCC, fit for radical chemoradiation were randomly assigned. Primary sites in the nasopharynx, salivary gland, nasal cavity, and paranasal sinus were excluded. Randomized 1:1 to either radical radiotherapy (66-70 Gy) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of chemoradiation with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was a 10-year OS; the key secondary endpoint was late adverse events. Intent to treat analysis was performed. OS was defined as the time from randomization till death. Kaplan Meier method will be used for the estimation of OS. Landmark analysis was performed to compare 10 OS between the 2 arms. COX proportional hazard model will be used for the calculation of hazard ratio (HR). The adverse events between the 2 arms were compared using a Fisher's test. A p-value of 0.05 will be considered as significant. Results: The median follow-up was 8.86 years (95% CI 8.59-9.16). The primary site of the primary was the oropharynx (269,50.2%) and only 24 cases were HPV positive. The 10-year OS was 22.5% (95% CI 16.7-28.8) versus 33.5% (95% CI 27.6-39.4) in the CRT and NCRT arm respectively (Hazard ratio=0.811; 95%CI 0.664-0.995, P=0.044). The median OS was 2.78 years (95% CI 2.31-3.69) versus 3.69 years (95% CI 2.90-4.49) in the CRT and NCRT arm respectively (P value by log-rank test=0.04). The median OS in HPV negative oropharynx was 1.8 years (95% CI 1.51-2.09) versus 2.48 years (95% CI 1.79-3.16) in the CRT and NCRT arm respectively (P value by log-rank test=0.02; HR 0.724 95%CI 0.546-0.959). Long-term adverse events were captured in 380 patients. There was no statistically significant difference in late-term adverse events between the 2 arms and will be presented at the conference. Conclusions: The addition of nimotuzumab to weekly cisplatin leads to improvement in long-term overall survival in locally advanced HNSCC without any additional increase in late-term adverse events. These results are largely applicable in HPV-negative patients. Clinical trial information: CTRI/2014/09/004980 .
Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study.
Authors: Solomon Benjamin J. , Liu Geoffrey , Felip Enriqueta , Mok Tony S. K. , Soo Ross Andrew , Mazieres Julien , Shaw Alice Tsang , de Marinis Filippo , Goto Yasushi , Wu Yi-Long , Kim Dong-Wan , Martini Jean-Francois , Messina Rossella , Paolini Jolanda , Polli Anna , Thomaidou Despina , Toffalorio Francesca , Bauer Todd Michael 
Published: June 2024

LBA8503 Background: Lorlatinib, a brain-penetrant, 3rd-generation ALK tyrosine kinase inhibitor, demonstrated improved progression-free survival (PFS) and intracranial (IC) activity vs crizotinib in the phase 3 CROWN study in treatment-naïve patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). We report long-term efficacy and safety outcomes from the CROWN study after 5 years of follow-up. Methods: 296 treatment-naïve pts with advanced ALK+ NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). In this post hoc analysis, we present investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing was not performed. Results: As of October 31, 2023, 74 of 149 pts (50%) vs 7 of 142 pts (5%) were still receiving lorlatinib vs crizotinib. With a median duration of follow-up for PFS (95% CI) of 60.2 months (57.4-61.6) in the lorlatinib and 55.1 months (36.8-62.5) in the crizotinib arm, median PFS (95% CI) was not reached (NR; 64.3-NR) with lorlatinib and 9.1 months (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). 5-year PFS (95% CI) was 60% (51-68) with lorlatinib and 8% (3-14) with crizotinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). In pts without baseline brain metastases in the lorlatinib arm, only 4 of 114 developed brain progression, occurring within the first 16 months of treatment. Efficacy outcomes by baseline brain metastases are shown in the Table. Grade 3/4 adverse events (AEs) occurred in 77% of pts with lorlatinib and in 57% of pts with crizotinib. Treatment-related AEs led to treatment discontinuation in 5% and 6% of pts in the lorlatinib and crizotinib arms, respectively. Safety profile was consistent with that observed in prior analyses. Emerging new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment (n = 31). Conclusions: After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC. Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for pts with advanced ALK+ NSCLC. Clinical trial information: NCT03052608 . [Table: see text]
Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.
Authors: Lorigan Paul , Medina Theresa , Nyakas Marta , Rutten Annemie , Feun Lynn G. , Cowey Charles Lance , Payne Miranda , Hussain Israr , Kuzel Timothy , O'Day Steven , Sheri Amna , Friedlander Philip Adam , Kumar Satish , Bjorheim Jens , Bechter Oliver Edgar 
Published: June 2024

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH >upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade >3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .
Quality of life with neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) versus adjuvant nivolumab in resectable stage III melanoma: 36-week data from the phase 3 NADINA trial.
Authors: Lucas Minke W. , Arokoski Reetta , Menzies Alexander M. , Pulleman Saskia , Saw Robyn P.M. , van Houdt Winan J. , Faries Mark B , Robert Caroline , Ascierto Paolo Antonio , Lebbe Celeste , Carlino Matteo S. , Kapiteijn Ellen , Suijkerbuijk Karijn , Rutkowski Piotr , Sandhu Shahneen , Van Der Veldt Astrid Aplonia Maria , Long Georgina V. , Blank Christian U. , van de Poll-Franse Lonneke , Lijnsvelt Judith 
Published: June 2024

LBA9584 Background: Neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) showed improved event-free survival compared to adjuvant (adj) NIVO, but at the cost of increased immune related toxicity (irAEs). In the PRADO trial, impairment of health-related quality of life (HRQoL) was predominantly driven by the extent of the surgery and not by irAEs. To evaluate the effect of neoadj IPI+NIVO on HRQoL, we report the 36w HRQoL outcomes from the phase 3 NADINA trial. Methods: Eligible patients (pts) with resectable, macroscopic stage III melanoma were randomly assigned to receive 2 cycles of neoadj IPI+NIVO followed by a therapeutic lymph node dissection (TLND; w6) and only in partial- or non-responders, 1y of adj systemic treatment; or TLND (w0) followed by 12 cycles adj NIVO. EORTC QLQ-C30 questionnaires (qtn) were digitally collected at baseline, w6, w12 and thereafter q12w. The unadjusted HRQoL scores (scale 0-100) were assessed for pts who completed 39w of follow-up (FU) on January 12, 2024. Results: 261/423 randomized pts had 39w FU at data cutoff. 81% completed the qtn at BL, with thereafter an average compliance of 80%. QLQ-C30 data were available for 107 pts in the neoadj arm and 103 in the adj arm. Physical-, role-, emotional functioning, and pain were comparable between the neoadj and adj arm across all timepoints (Table), as were fatigue and the summary score. A numerical trend towards worsening of physical-, role functioning, and pain was seen at w6 for the adj arm and at w12 for the neoadj arm, representing the post-surgery QoL timepoints. Conclusion: Using fully digitalized data collection, this first HRQoL analysis of neoadj vs adj immunotherapy in stage III melanoma showed comparable results between the neoadj and adj arms. Physical-, role functioning, and pain were impaired in both groups at the first post-surgery timepoint. Clinical trial information: NCT04949113 . [Table: see text]
Impact of a Multidisciplinary Supportive Care Model Using Distress Screening at an Asian Ambulatory Cancer Center: A Cluster Randomized Controlled Trial
Authors: Ke Yu , Neo Patricia Soek Hui , Yang Grace Meijuan , Neo Shirlyn Hui-Shan , Tan Yung Ying , Tan Yee Pin , Ramalingam Mothi Babu , Loh Kiley Wei-Jen , Quah Daniel Song Chiek , Chew Lita , Si Phebe En Hui , Chan Raymond Javan , Hwang William Ying Khee , Chan Alexandre 
Published: June 2024

PURPOSE The Accessible Cancer Care to Enable Support for Cancer Survivors (ACCESS) program adopts a multidisciplinary supportive care model with routine distress screening to triage newly diagnosed cancer survivors for additional support on the basis of distress levels. This study aimed to evaluate the clinical impact of ACCESS over 1 year. METHODS We performed cluster random assignment at the oncologist level in a 1:1 ratio to receive ACCESS or usual care. Participants 21 years and older, newly diagnosed with breast or gynecologic cancer, and receiving care at National Cancer Centre Singapore were included. Outcomes assessed every 3 months for 1 year included quality of life (QoL) (primary), functioning, physical and psychological symptom burden, and activity levels. Data were analyzed using mixed-effects models. RESULTS Participants from 16 clusters (control = 90, intervention = 83) were analyzed. The ACCESS program did not significantly improve QoL (primary outcome). However, compared with usual care recipients, ACCESS recipients reported higher physical functioning ( P = .017), role functioning ( P = .001), and activity levels ( P < .001) at 9 months and lower psychological distress ( P = .025) at 12 months. ACCESS recipients screened with high distress had poorer QoL, lower role and social functioning, and higher physical symptom distress at 3 months but had comparable scores with ACCESS recipients without high distress after 12 months. CONCLUSION Compared with usual care, participation in the ACCESS program did not yield QoL improvement but showed earlier functioning recovery related to activities of daily living and reduced psychological distress. Routine distress screening is a promising mechanism to identify survivors with poorer health for more intensive supportive care.
Exact classical approach to the electron's self-energy and anomalous g-factor
Authors: Georgiev M. 
Published: June 2024

Abstract
An exact classical approach to the calculation of electron's self-energy and anomalous g-factor is reported. The electron's intrinsic dynamics, related electrodynamics and occurrence of anomalous magnetic moment are completely determined. A unique regularization of the electromagnetic field scalar potential underlying all results is derived. A fundamental transcendental equation satisfied by the electron's anomalous g-factor is obtained, with solution

, matching the experimentally measured value reported in the literature to 0.59 parts per trillion. Field representation of the electron intrinsic and orbital dynamics in atoms is discussed.
Machine Learning Reveals the Contribution of Lipoproteins to Liver Triglyceride Content and Inflammation
Authors: Tavaglione Federica , Marafioti Giuseppe , Romeo Stefano , Jamialahmadi Oveis 
Published: June 2024

Abstract

Context
Metabolic dysfunction–associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide and is strongly associated with metabolic comorbidities, including dyslipidemia.

Objective
Herein, we aim to estimate the prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in Europeans with isolated hypercholesterolemia and isolated hypertriglyceridemia in the UK Biobank and to estimate the independent contribution of lipoproteins to liver triglyceride content.

Methods
We selected 218 732 Europeans from the UK Biobank without chronic viral hepatitis and other causes of liver disease, of whom 14 937 with liver magnetic resonance imaging data available. Next, to examine the relationships between traits in predicting liver triglyceride content, we compared the predictive performance of several machine learning methods and selected the best performing algorithms based on the minimum cross-validated mean squared error (MSE).

Results
There was an approximately 3-fold and 4-fold enrichment of MASLD and MASH in individuals with isolated hypertriglyceridemia (P = 1.23 × 10–41 and P = 1.29 × 10–10, respectively), whereas individuals with isolated hypercholesterolemia had a marginal higher rate of MASLD and no difference in MASH rate compared with the control group (P = .019 and P = .97, respectively). Among machine learning methods, the feed-forward neural network had the best cross-validation MSE on the validation set. Circulating triglycerides, after body mass index, were the second strongest independent predictor of liver proton density fat fraction with the largest absolute mean Shapley additive explanation value.

Conclusion
Isolated hypertriglyceridemia is the second strongest, after obesity, independent predictor of MASLD/MASH. Individuals with hypertriglyceridemia, but not with hypercholesterolemia, should be screened for liver disease.
Teprotumumab for the Treatment of Thyroid Eye Disease
Authors: Ugradar Shoaib , Malkhasyan Emil , Douglas Raymond S 
Published: June 2024

Abstract
Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves’ disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED, chemosis, lid swelling, proptosis, and diplopia, are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that 1 of the major drivers of this molecular signature is the overexpression of the IGF-1 receptor [IGF-1R]) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human IgG1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the United States for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia, and burden on quality of life in patients who were treated. Postintroduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, more than 5800 patients have been treated with teprotumumab, and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first-line therapy for patients with moderate to severe TED who display features of proptosis and diplopia.
Interhemispheric and Corticothalamic White-Matter Dysfunction Underlies Affective Morbidity and Impaired Pain Modulation in Chronic Pain
Authors: Ito Atsushi , Yang Sushuang , Shinto Eri , Shinto Atsushi , Toyofuku Akira , Kurata Jiro 
Published: June 2024

BACKGROUND:
Although patients with chronic pain show behavioral signs of impaired endogenous pain modulation, responsible cerebral networks have yet to be anatomically delineated. We used diffusion tensor imaging (DTI) to examine the white-matter alterations in patients with chronic pain compared with healthy subjects. We further measured thermal pain modulatory responses using the offset analgesia (OA) paradigm. We tested whether the white-matter indices be associated with psychophysical parameters reflecting morbidity and modulatory responses of pain in patients, and whether they could serve as diagnostic biomarkers of chronic pain.

METHODS:
Twenty-six patients with chronic pain and 18 age- and gender-matched healthy controls were enrolled. After completing psychophysical questionnaires, they underwent OA measurement and whole-brain DTI in a 3 Tesla magnetic resonance imaging scanner. Fractional anisotropy (FA) and radial diffusivity (RD) of the white-matter were computed and compared between the groups with tract-based spatial statistics using the FMRIB Software Library (FSL) software. Correlations were sought among white-matter indices, thermal pain responses, and psychophysical parameters. The white-matter indices and OA-related parameters were tested whether they distinguish patients from controls by receiver operating characteristic analysis.

RESULTS:
During OA, patients showed a shorter latency to the maximum (maximum visual analog scale [VAS] latency, 16.0 ± 3.7 vs 18.9 ± 3.1 second [mean ± standard deviation, SD]; P = .032) but a longer latency to the minimum pain (OA latency, 15.6 ± 3.5 vs 11.1 ± 4.2 seconds; P = .004) than controls. They showed a smaller mean FA (0.44 ± 0.12 vs 0.45 ± 0.11; P = .012) and a larger mean RD of the global white-matter (0.00057 ± 0.00002 vs 0.00056 ± 0.00002; P = .038) than controls, at specific areas including the corpus callosum, anterior thalamic radiation, and forceps major. FA of the splenium of the corpus callosum was associated with maximum VAS latency (r = 0.493) and OA latency (r = −0.552). The Pain Catastrophizing Scale scores showed strong negative correlations with FA across those specific areas (r = −0.405). Those latencies during OA and white-matter metrics distinguished patients from controls (P < .05).

CONCLUSIONS:
Patients with chronic pain showed dysfunction of the white matter concerned with interhemispheric communication of sensorimotor information as well as descending corticothalamic modulation of pain in association with affective morbidity and altered temporal dynamics of pain perception. We suggest that an impaired interhemispheric modulation of pain, through the corpus callosum, might be a novel cerebral mechanism in chronification of pain.
Regime Type and Data Manipulation: Evidence from the COVID-19 Pandemic
Authors: Wigley Simon 
Published: June 2024

Abstract
Context: This study examines whether autocratic governments are more likely than democratic governments to manipulate health data. The COVID-19 pandemic presents a unique opportunity for examining this question because of its global impact.
Methods: Three distinct indicators of COVID-19 data manipulation were constructed for nearly all sovereign states. Each indicator was then regressed on democracy and controls for unintended misreporting. A machine learning approach was then used to determine whether any of the specific features of democracy are more predictive of manipulation.
Findings: Democracy was found to be negatively associated with all three measures of manipulation, even after running a battery of robustness checks. Absence of opposition party autonomy and free and fair elections were found to be the most important predictors of deliberate undercounting.
Conclusions: The manipulation of data in autocracies denies citizens the opportunity to protect themselves against health risks, hinders the ability of international organizations and donors to identify effective policies, and makes it difficult for scholars to assess the impact of political institutions on population health. These findings suggest that health advocates and scholars should use alternative methods to estimate health outcomes in countries where opposition parties lack autonomy or must participate in uncompetitive elections.