bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-treatment peripheral blood immunophenotyping and response to neoadjuvant chemotherapy in operable breast cancer
Authors: Leon-Ferre Roberto A. , Whitaker Kaitlyn R. , Suman Vera J. , Hoskin Tanya , Giridhar Karthik V. , Moore Raymond M. , Al-Jarrad Ahmad , McLaughlin Sarah A. , Northfelt Donald W. , Hunt Katie N. , Conners Amy Lynn , Moyer Ann , Carter Jodi M. , Kalari Krishna , Weinshilboum Richard , Wang Liewei , Ingle James N. , Knutson Keith L. , Ansell Stephen M. , Boughey Judy C. , Goetz Matthew P. , Villasboas Jose C.
Published: June 2024

Background

Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied.

Methods

Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal–Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC.

Results

There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response.

Conclusions

Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer.

Trial registration

NCT02022202. Registered 20 December 2013.
CelFiE-ISH: a probabilistic model for multi-cell type deconvolution from single-molecule DNA methylation haplotypes
Authors: Unterman Irene , Avrahami Dana , Katsman Efrat , Triche Timothy J. , Glaser Benjamin , Berman Benjamin P.
Published: June 2024

Deconvolution methods infer quantitative cell type estimates from bulk measurement of mixed samples including blood and tissue. DNA methylation sequencing measures multiple CpGs per read, but few existing deconvolution methods leverage this within-read information. We develop CelFiE-ISH, which extends an existing method (CelFiE) to use within-read haplotype information. CelFiE-ISH outperforms CelFiE and other existing methods, achieving 30% better accuracy and more sensitive detection of rare cell types. We also demonstrate the importance of marker selection and of tailoring markers for haplotype-aware methods. While here we use gold-standard short-read sequencing data, haplotype-aware methods will be well-suited for long-read sequencing.
Prediction models for amputation after diabetic foot: systematic review and critical appraisal
Authors: Huang Jingying , Yang Jin , Qi Haiou , Xu Miaomiao , Xu Xin , Zhu Yiting
Published: June 2024

Background

Numerous studies have developed or validated prediction models aimed at estimating the likelihood of amputation in diabetic foot (DF) patients. However, the quality and applicability of these models in clinical practice and future research remain uncertain. This study conducts a systematic review and assessment of the risk of bias and applicability of amputation prediction models among individuals with DF.

Methods

A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, EBSCO CINAHL Plus, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedical Literature Database (CBM), and Weipu (VIP) from their inception to December 24, 2023. Two investigators independently screened the literature and extracted data using the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies. The Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist was employed to evaluate both the risk of bias and applicability.

Results

A total of 20 studies were included in this analysis, comprising 17 development studies and three validation studies, encompassing 20 prediction models and 11 classification systems. The incidence of amputation in patients with DF ranged from 5.9 to 58.5%. Machine learning-based methods were employed in more than half of the studies. The reported area under the curve (AUC) varied from 0.560 to 0.939. Independent predictors consistently identified by multivariate models included age, gender, HbA1c, hemoglobin, white blood cell count, low-density lipoprotein cholesterol, diabetes duration, and Wagner’s Classification. All studies were found to exhibit a high risk of bias, primarily attributed to inadequate handling of outcome events and missing data, lack of model performance assessment, and overfitting.

Conclusions

The assessment using PROBAST revealed a notable risk of bias in the existing prediction models for amputation in patients with DF. It is imperative for future studies to concentrate on enhancing the robustness of current prediction models or constructing new models with stringent methodologies.
Understanding stakeholder attitudes towards low-head pumped hydro storage technology
Authors: Ansorena Ruiz Ruben , Schürenkamp David , Bricker Jeremy D. , Olvermann Madita , Goseberg Nils
Published: June 2024

Background

The share of renewable energy feeding the European grid has been growing over the years, even though the intermittency of some renewable energy sources can induce electric grid instability. Energy storage has proven to be an effective way of reducing grid instability. Various solutions for large-scale energy storage are being researched nowadays. This study focusses on the innovative low-head pumped hydro storage (LH PHS) technology, a large-scale energy storage scheme suitable for shallow seas (5 – 30 m depth). Implementation of renewable energy technologies, such as wind farms in Europe, Asia and North America, has faced public opposition which has delayed or even cancelled the implementation of renewable energy projects. Literature about public perception of projects highlights the importance of involving stakeholders from the early stages of project planning. Considering this, the present study aims to collect stakeholder opinions (via an online survey) to determine what is necessary for a smooth implementation of LH PHS in the North Sea, both from technical and policy points of view.

Results

Stakeholders from commercial parties, government authorities and local groups recognized the potential of LH PHS as a means to increase the share of renewable energies within the European power grid. Economics, bureaucratic burden, and structural safety have emerged as primary aspects of concern respecting the implementation of LH PHS. The impression of the respondents is that a low-head pumped hydro station would not have negative effects on their organizations. Furthermore, most of the engineering firms participating in the study communicated that their knowledge and resources could be involved in the construction of such an energy storage facility.

Conclusion

As identified stakeholder concerns such as economics and structural safety are currently being researched, effective communication of the findings of this research is paramount to keep stakeholders informed of the ongoing progress. Two-way communication between researchers and stakeholders is recommended to enhance public acceptance of future technologies. Furthermore, is it advisable to undertake an examination of the available energy policies relevant to LH PHS.
A comprehensive exploration of astrocytes in migraine: a bibliometric and visual analysis
Authors: Wei Shijie , Du Tianqi , Zhang Lili , Li Xuhao , Wang Zhe , Ning Yike , Tang Yu , Wu Xinyu , Han Jing
Published: June 2024

Background

Migraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology.

Methods

On November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers.

Results

As of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences.

Conclusions

Future investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.
How to treat mixed behavior segments in supervised machine learning of behavioural modes from inertial measurement data
Authors: Resheff Yehezkel S. , Bensch Hanna M. , Zöttl Markus , Harel Roi , Matsumoto-Oda Akiko , Crofoot Margaret C. , Gomez Sara , Börger Luca , Rotics Shay
Published: June 2024

The application of supervised machine learning methods to identify behavioural modes from inertial measurements of bio-loggers has become a standard tool in behavioural ecology. Several design choices can affect the accuracy of identifying the behavioural modes. One such choice is the inclusion or exclusion of segments consisting of more than a single behaviour (mixed segments) in the machine learning model training data. Currently, the common practice is to ignore such segments during model training. In this paper we tested the hypothesis that including mixed segments in model training will improve accuracy, as the model would perform better in identifying them in the test data. We test this hypothesis using a series of data simulations on four datasets of accelerometer data coupled with behaviour observations, obtained from four study species (Damaraland mole-rats, meerkats, olive baboons, polar bears). Results show that when a substantial proportion of the test data are mixed behaviour segments (above ~ 10%), including mixed segments in machine learning model training improves the accuracy of classification. These results were consistent across the four study species, and robust to changes in segment length, sample size, and degree of mixture within the mixed segments. However, we also find that in some cases (particularly in baboons) models trained with mixed segments show reduced accuracy in classifying test data containing only single behaviour (pure) segments, compared to models trained without mixed segments. Based on these results, we recommend that when the classification model is expected to deal with a substantial proportion of mixed behaviour segments (> 10%), it is beneficial to include them in model training, otherwise, it is unnecessary but also not harmful. The exception is when there is a basis to assume that the training data contains a higher rate of mixed segments than the actual (unobserved) data to be classified—such a situation may occur particularly when training data are collected in captivity and used to classify data from the wild. In this case, excess inclusion of mixed segments in training data should probably be avoided.
Stand diversity increases pine resistance and resilience to compound disturbance
Authors: Germain Sara J. , Lutz James A.
Published: June 2024

Background

Drought, fire, and insects are increasing mortality of pine species throughout the northern temperate zone as climate change progresses. Tree survival may be enhanced by forest diversity, with growth rates often higher in mixed stands, but whether tree defenses are likewise aided remains in question. We tested how forest diversity-productivity patterns relate to growth and defense over three centuries of climate change, competition, wildfire, and bark beetle attack. We used detailed census data from a fully mapped 25.6-ha forest dynamics plot in California, USA to conduct a spatially explicit, dendroecological assessment of large-diameter Pinus lambertiana survival following fire reintroduction. Our structural equation models investigated direct and indirect pathways by which growth, defense, and forest composition together mediated pine resistance and resilience.

Results

In the historical era of frequent, mixed-severity fire (pre-1900), trees that were ultimately resistant or susceptible to the post-fire bark beetle epidemic all showed similar growth and defenses, as measured by axial resin duct traits. During the era of fire exclusion (1901–2012), however, susceptible trees had slower growth. Following fire re-entry in 2013, both growth and defense declined precipitously for susceptible trees, resulting in fatal bark beetle attack. Spatial analysis showed that monodominant crowding by shade-tolerant competitors contributed to the long-term stress that prevented susceptible trees from recuperating defenses quickly following fire re-entry. For beetle-resistant trees, however, we found positive feedbacks between diversity, growth, and survival: trees in species-rich communities had higher growth rates pre-fire, which promoted a rapid recuperation of defenses following fire that helped trees resist bark beetle attack. Overall, this associational resistance outweighed associational susceptibility (+8.6% vs. −6.4% change in individual tree survival odds), suggesting a relaxation effect that ultimately allowed 58% of large pines to survive.

Conclusions

Though climate change threatens forest biodiversity, biodiversity is key to forest climate adaptation in return. Our findings demonstrate centennial-scale feedbacks by which forest diversity increases pine resistance and resilience to climate-amplified disturbances. The spatially explicit, dendroecological framework provides new insights into diversity-productivity theory, while also informing climate-adaptive forest management by identifying thresholds of tree density and richness that maximize large pine survival.
Silencing circ-RNA-049637 influences hydatid outer cyst wall formation by liver fibrosis
Authors: Kalifu Baheti , Meng Yuan , Ma Zhi-Gang , Ma Chao , Tian Guang-Lei , Wang Jin-Guo , Chen Xiong
Published: June 2024

Introduction and objectives

In diseases characterized by fibrosis, hepatic stellate cells (HSCs) are mesenchymal cells that play an important role in liver fibrosis. circRNAs are involved in regulating hydatid exocyst formation through miRNA sponge adsorption. The mechanisms of hepatic cystic hydatid outer cyst formation, HSC, and liver fibrosis are unclear.

Materials and methods

Based on our sequencing data, we validated the mechanism by which circRNA-049637 regulated hepatic cystic hydatid growth and promoted outer fibrocystic wall formation.

Results

Our results revealed that circRNA_049637 silencing promoted the proliferation of LX-2 human HSCs, affected the cell cycle, and increased the mRNA and protein expression levels of liver fibrosis-related indicators such as α-SMA, COL1A1, COL3A1, and TGFβRII.

Conclusions

CircRNA_049637 may induce the formation of hepatic hydatid cysts by promoting hepatic fibrosis via HSC activation.
The new neural pressure support (NPS) mode and the helmet: did we find the dynamic duo?
Authors: Costa Alessandro , Merlo Federico , Pagni Aline , Navalesi Paolo , Grasselli Giacomo , Cammarota Gianmaria , Colombo Davide
Published: June 2024

Background

Noninvasive ventilation (NIV) is commonly used in clinical practice to reduce intubation times and enhance patient comfort. However, patient-ventilator interaction (PVI) during NIV, particularly with helmet interfaces, can be challenging due to factors such as dead space and compliance. Neurally adjusted ventilatory assist (NAVA) has shown promise in improving PVI during helmet NIV, but limitations remain. A new mode, neural pressure support (NPS), aims to address these limitations by providing synchronized and steep pressurization. This study aims to assess whether NPS per se improves PVI during helmet NIV compared to standard pressure support ventilation (PSV).

Methods

The study included adult patients requiring NIV with a helmet. Patients were randomized into two arms: one starting with NPS and the other with PSV; the initial ventilatory parameters were always set as established by the clinician on duty. Physiological parameters and arterial blood gas analysis were collected during ventilation trials. Expert adjustments to initial ventilator settings were recorded to investigate the impact of the expertise of the clinician as confounding variable. Primary aim was the synchrony time (Timesync), i.e., the time during which both the ventilator and the patient (based on the neural signal) are on the inspiratory phase. As secondary aim neural-ventilatory time index (NVTI) was also calculated as Timesyncdivided to the total neural inspiratory time, i.e., the ratio of the neural inspiratory time occupied by Timesync.

Results

Twenty-four patients were enrolled, with no study interruptions due to safety concerns. NPS demonstrated significantly longer Timesync(0.64 ± 0.03 s vs. 0.37 ± 0.03 s,p < 0.001) and shorter inspiratory delay (0.15 ± 0.01 s vs. 0.35 ± 0.01 s,p < 0.001) compared to PSV. NPS also showed better NVTI(78 ± 2% vs. 45 ± 2%,p < 0.001). Ventilator parameters were not significantly different between NPS and PSV, except for minor adjustments by the expert clinician.

Conclusions

NPS improves PVI during helmet NIV, as evidenced by longer Timesyncand better coupling compared to PSV. Expert adjustments to ventilator settings had minimal impact on PVI. These findings support the use of NPS in enhancing patient-ventilator synchronization and warrant further investigation into its clinical outcomes and applicability across different patient populations and interfaces.

Trial registration

This study was registered onwww.clinicaltrials.govNCT06004206 Registry URL:https://clinicaltrials.gov/study/NCT06004206on September 08, 2023.
Phase III randomized trial of intensity-modulated proton therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for the treatment of head and neck oropharyngeal carcinoma (OPC).
Authors: Frank Steven J. , Busse Paul , Rosenthal David Ira , Hernandez Mike , Swanson David Michael , Garden Adam S. , Sturgis Erich M. , Ferrarotto Renata , Gunn Gary Brandon , Patel Samir H , LEE NANCY Y. , Lin Alexander , Snider James W , McDonald Mark William , Henson Christina , Bajaj Gopal Krishna , Kalman Noah , Parvathaneni Upendra , Katz Sanford R. , Foote Robert Leonard ,   MD Anderson Clinical Trial Consortium
Published: June 2024

6006

Background: IMPT has unique biologic and physical properties compared with IMRT, limits radiation dose beyond the targeted tumor volumes, and is a novel de-intensification strategy for the management of head and neck tumors. This study was designed to compare the outcomes for patients with OPC after chemoradiation therapy (CRT) with IMRT vs IMPT. Methods: This is a multi-center, randomized, phase III non-inferiority OPC trial Stage III/IV (AJCC 7th) squamous cell carcinoma stratified patients by human papillomavirus status, smoking status, and receipt of induction chemotherapy (IC). The primary endpoint was the rate of progression-free survival (PFS) rate at 3 years, where progression was defined as disease recurrence or death. Under the null hypothesis, H0: r ≥ 1.535 established the margin for non-inferiority of IMPT. Secondary endpoints include overall survival (OS), treatment-related malnutrition, and gastrostomy-tube dependence. Analyses were conducted on intent-to-treat (ITT; n=440), per-protocol (PP; n=296), and as-treated (AT; n=397) populations. Results: Patients (n=440) were randomized to undergo IMRT(n=219) or IMPT (n=221) at 21 institutions. The median age was 61 years and HPV/p16 was positive in 95%. IC was the initial treatment in 13% of patients. All patients were treated with CRT to 70 Gy in 33 fx with bilateral neck treatment, and post-CRT surgical lymph node dissection occurred in 8%. The median follow-up was 3.14 years. In the ITT analysis, the hazard ratio (HR) for disease progression or death at 3 y was 0.87 (95%CI 0.56,1.35); p=0.006 and the corresponding HR for death (OS) was 0.63 (95%CI 0.36-1.10) suggesting a protective affect with IMPT. In PP analysis, the PFS HR was 0.85 (95%CI 0.52,1.38); p=0.009 and HR for death (OS) was 0.60 (95%CI 0.32-1.12). In the AT analysis, PFS HR was 0.88 (95%CI 0.56,1.37); p=0.007 and the corresponding HR for death (OS) was 0.70 (95%CI 0.40-1.22). For each analysis above, the null hypothesis was rejected and IMPT was non-inferior to IMRT. PP gastrostomy-tube dependence decreased with IMPT vs. IMRT from 42% to 28% (p=0.019), and more IMPT patients sustained their nutrition with end of treatment weight loss < 5% from baseline: 24% vs 14% (p=0.037). Conclusions: IMPT is non-inferior to IMRT and has emerged as a standard of care CRT approach for OPC that reduces malnutrition and gastrostomy-tube dependence. Clinical trial information: NCT01893307 .
BMI correlation with outcomes in patients with head and neck cancer undergoing immunotherapy: A comprehensive review and meta-analysis.
Authors: Saowapa Sakditad , Wannaphut Chalothorn , Tanariyakul Manasawee , Wattanachayakul Phuuwadith , Siladech Pharit , Polpichai Natchaya , Tijani Lukman Aderoju
Published: June 2024

6021

Background: Currently, the landscape of treating advanced malignancies has undergone a transformative shift with the advent of immunotherapy employing immune checkpoint inhibitors (ICIs). Notably, several ICIs have emerged as promising therapeutic modalities for individuals with head and neck cancer (HNC). An emerging body of evidence implies a plausible link between body mass index (BMI) and the effectiveness of ICIs in the broader context of cancer patients. Nevertheless, the specific correlation within the subset of head and neck cancer patients undergoing immunotherapeutic interventions remains unclear and warrants meticulous investigation. Methods: PubMed, Web of Science, and Google Scholar databases were searched extensively for records published until January 2024. Full-text articles aligned with the research objective were included, while records published in English, case reports, reviews, editorials, and studies reporting immunotherapy combined with other cancer therapies were excluded. The data required for review and analysis was abstracted in Excel files by two independent reviewers. Additionally, statistical analyses were performed using the Review Manager software, and methodological quality was assessed using the Newcastle Ottawa scale. Results: Only six studies were eligible for review and analysis. A subgroup analysis of data from these studies showed that obese HNC patients on immunotherapy had significantly better overall survival (OS) rates than non-obese patients (HR: 0.51; 95% CI: 0.29 – 0.93; p=0.03). However, the progression-free survival (PFS) was statistically similar between obese and non-obese patients (HR: 0.72; 95% CI: 0.39 – 1.33; p=0.30). In addition, when BMI was stratified as either low or high, no significant difference was observed in the OS and PFS of HNC patients (HR: 0.99; 95% CI: 0.59 – 1.66; p=0.97 and HR: 0.93; 95% CI: 0.61 – 1.41; p=0.42, respectively). Similarly, the statistical analyses showed that overweight patients have similar OS and PFS as patients with normal BMI (HR: 0.53; 95% CI: 0.15 – 1.92; p=0.33 and HR: 0.55; 95% CI: 0.20 – 1.52; p = 0.25, respectively). In contrast, underweight patients demonstrated poor OS and PFS (HR: 2.56; 95% CI: 1.29 – 5.12; p=0.008 and HR: 2.76; 95% CI: 1.17 – 6.52; p=0.02, respectively). Conclusions: Obese HNC patients on immunotherapy tend to have improved OS than non-obese patients, while underweight patients have worse clinical prognoses than those with normal or above BMI.
Validation of HLA presented tumor-exclusive peptides in an independent cohort of head and neck squamous cell carcinoma.
Authors: Laban Simon , Schröder Sarah , Mühlenbruch Lena , von Witzleben Adrian , Abou Kors Tsima , Brunner Cornelia , Maringer Yacine , Nelde Annika , Hönisch Gravel Naomi , Scheid Jonas , Dubbelaar Marissa L , Gross Thorben , Kraus Johann M. , Kestler Hans A. , Mauz Paul-Stefan , Löwenheim Hubert , Greve Jens , Hoffmann Thomas K , Rammensee Hans-Georg , Walz Juliane S.
Published: June 2024

6047

Background: Response rates to anti-PD1 antibodies in head and neck squamous cell carcinoma (HNSCC) range from 13-20% in recurrent / metastatic disease and up to 50% in locoregionally advanced disease. Vaccines composed of tumor-exclusive antigens may increase response rates to immunotherapy. We have previously identified HLA-presented tumor-exclusive peptides (TEP) in a cohort of 40 oropharyngeal HNSCC (UL dataset) and defined a warehouse of HLA allotype specific TEP (EP2023/071063, patent pending) for semipersonalized vaccine composition for 15 HLA allotypes. Methods: The HLA-bound immunopeptidome of a validation cohort of 40 HNSCC from Tübingen University was analyzed by tandem mass spectrometry (TÜ dataset). Data were processed as previously described to identify TEP. The TÜ dataset was queried for TEP from the previously defined warehouse containing 48 TEP for the respective 15 HLA allotypes in a cohort of 40 oropharyngeal HNSCC (UL dataset) patient samles. Coverage was defined as the fraction of patients presenting at least one of the TEP for a certain HLA allotype. Results: Among all 80 patients, 75 had at least one of the 15 HLA allotypes (36 in the TÜ cohort and 39 in the UL cohort). Of the 48 TEP, 28 TEP for 11/15 HLA allotypes were found in the TÜ validation cohort. The best coverages with the warehouse TEP were found for the following four HLA allotypes: HLA-A*01:01 (TÜ: 91%; UL: 79%), A*02:01 (TÜ: 81%; UL: 52%), B*40:01 (TÜ: 63%; UL: 100%) and A*24:02 (TÜ: 60%; 44%.). Based on a semipersonalized TEP selection by HLA allotype, 27/40 patients in the TÜ cohort presented at least one of the TEP selected (range: 0-10), whereas 28/40 patients in the UL cohort presented at least one of the TEP (range: 0-7). Thus, the total cohort coverage based on a semipersonalized peptide selection was 55/80 patients (68.8%). Conclusions: We validated previously identified TEP from oropharyngeal HNSCC for frequently occurring HLA allotypes in an independent, equally sized cohort of HNSCC patients. A semipersonalized vaccine composition strategy using a warehouse / off-the-shelve approach for immunotherapy trials seems feasible.
Neoadjuvant immunotherapy for oropharynx cancer: Correlative studies and long-term outcomes from the CIAO trial.
Authors: McGrail Daniel , Li Kaiyi , Nipper Allison , Johnson Faye M. , Santana Erison , Bell Diana , Lee Minjung , Haymaker Cara L , Garden Adam S. , Lin Shiaw-Yih , Lee J. Jack , Gillison Maura L. , Gross Neil D. , Sikora Andrew G. , Ferrarotto Renata
Published: June 2024

6059

Background: CIAO (Checkpoint Inhibitors Assessment in Oropharynx cancer) was a window of opportunity trial evaluating the anti-PD-L1 durvalumab (durva) with or without the anti-CTLA-4 tremelimumab (treme) prior to surgery in 28 oropharynx squamous cell carcinoma (OPC) patients (pts). Here we report correlative analyses and long-term survival outcomes. Methods: A total of 28 OPC pts were randomized to receive durva (n=14) or durva plus treme (n=14) for 2 cycles prior to surgery. Adjuvant radiotherapy with or without concomitant chemotherapy was recommended based on pathology findings, per standard of care. Efficacy and safety results have been previously reported. Whole exome sequencing (WES), RNA sequencing (seq), and TCR-seq were performed on available pre- and post-treatment primary tumor specimens. Circulating HPV was quantified pre-treatment and longitudinally. Associations with objective response (OR) to therapy per RECIST were determined using either Fisher’s exact test (binary variables) or rank-sum test (continuous variables). Multiple comparisons were corrected for by the Benjamini and Hochberg method. Disease-free survival (DFS) was defined as the time from surgery to recurrence or death. Results: Of the 28 enrolled pts, 20 were newly diagnosed and 8 had locoregional recurrent disease; 25 were HPV-positive. The OR rate per RECIST was 43%. Efficacy was equivalent in both arms. Responders tended to be of younger age (p=0.02). At the DNA level, baseline tumor mutation burden was not associated with response, but mutational contraction post-treatment was more often observed among responders (p=0.02). There were no statistically significant differentially expressed genes between responders and non-responders, however, immune deconvolution revealed that a low inferred tumor neutrophil-to-leukocyte ratio was associated with response (p=0.01). TCR-seq revealed 8 TCR motifs enriched in responders at 25% false discovery rate. Serum HPV levels significantly decreased in responders after treatment (p=0.02). With a median follow-up from surgery of 59.6 months (range 14.9-71.5 months; data cut-off 1/19/24), none of the 20 patients with newly diagnosed OPC had recurrence and all remain alive at the last contact date (DFS=100%). Of the 9 patients with recurrent OPC, 3 had subsequent distant recurrence and died of disease (median DFS=5.7 years, overall DFS=66.7%). Conclusions: Responses to neoadjuvant checkpoint inhibitors was associated with tumor mutational contraction and a low baseline neutrophil-to-leukocyte ratio in OPC. Eight TCR motifs were enriched in responders. Serum HPV level dynamics was associated with tumor burden and may be useful in response monitoring. DFS outcomes were favorable in both newly diagnosed and recurrent cohorts.
A prospective multicenter trial of dose escalation for weekly gemcitabine concurrent with intensity-modulated radiotherapy following cisplatin and gemcitabine induction chemotherapy in patients with locally advanced nasopharyngeal carcinoma.
Authors: Qi Zeng , Lin Bingqin , Li Fangming , Liu Yumeng , Wang Siyang , Deng Feiqiang , Lei Shaona
Published: June 2024

6071

Background: Gemcitabine and cisplatin induction chemotherapy, followed by cisplatin-based concurrent chemoradiotherapy, constitutes the standard treatment for locally advanced nasopharyngeal carcinoma (LANPC). However, the substantial cumulative dosage of cisplatin used in this approach renders it intolerable for many patients due to advanced age or compromised renal function. Therefore, identifying alternative chemotherapeutic agents is crucial. Gemcitabine is a potent radiosensitizer with an overall favorable safety profile. Despite extensive research on the maximum tolerated dose (MTD) of concurrent gemcitabine chemotherapy in head and neck cancer, its MTD as a single-agent chemotherapy concurrently administered with intensity-modulated radiotherapy (IMRT) in LANPC remains uncertain. Methods: Patients diagnosed with stage III-IVa nasopharyngeal carcinoma were prospectively enrolled in three hospitals located within the largest NPC endemic area in southern China. After two cycles of cisplatin plus gemcitabine induction chemotherapy, patients underwent combined concurrent radiochemotherapy (70 Gy/6-7 weeks) with weekly gemcitabine. The initial dose level was set at 25mg/m2 and subsequently escalated in a sequential manner to higher doses of 50mg/m2, 100mg/m2, 200mg/m2, and 300mg/m2 etc. Our study employed a dose escalation strategy in which the dosage was incremented to the next group only if no more than one out of six patients experienced Dose-Limiting Toxicity (DLT), until DLT occurred in at least two patients. Patients underwent follow-up evaluations every three months. This study is registered with ClinicalTrials.gov under NCT04522050. Results: Between October 2018 and December 2023, a total of 39 Chinese patients were enrolled, 36 (27 males, 9 females) patients were considered evaluable. The incidence of DLT was observed in two out of six patients receiving a dosage level of 300 mg/m², with both cases presenting Grade 3 oral mucositis. Subsequently, the study was replicated using the same dosage level, resulting again in two instances of DLT: one case with Grade 3 radiation dermatitis and another case with oral mucositis. Consequently, a reduced dosage level of 200mg/m² was determined as MTD. No significant hematological toxicity or serious gastrointestinal adverse events were observed. Tumor response evaluation by MRI after twelve weeks of IMRT showed a complete response rate of 100%. To date, only two cases (5.56%) have been reported exhibiting tumor recurrence. Conclusions: The MTD for weekly gemcitabine with IMRT following induction chemotherapy in LANPC is determined to be 200 mg/m2. The DLT associated with this treatment regimen primarily consists of radiation dermatitis and/or oral mucositis. Clinical trial information: NCT04522050 .
Induction chemotherapy effects on very advanced (T3/T4) human papillomavirus-related oropharyngeal cancer for participation in hypoxia-directed major de-escalation (30 Gy) definitive treatment trial.
Authors: Sherman Eric Jeffrey , Riaz Nadeem , Dunn Lara , Schöder Heiko , Wray Rick , Ganly Ian , Boyle Jay , Patel Snehal G. , Givi Babak , Fetten James Vincent , Wong Winston , Hung Tony , Kriplani Anuja , Zakeri Kaveh , Gelblum Daphna Y. , Yu Yao , Chen Linda , Shamseddine Achraf , Wong Richard J. , LEE NANCY Y.
Published: June 2024

6076

Background: De-escalation trials in human papillomavirus associated oropharyngeal carcinoma (HPV+ OPC) often exclude patients with very locally advanced disease. We previously demonstrated in a Phase II study that for patients with T1-T2 HPV+OPC that de-escalation to 30Gy of definitive chemoradiation based on lack of hypoxia on 18F-FMISO (fluoromisonidazole) PET (ROC Study) is associated with excellent outcomes (JNCI 2021; JCO 2024). Here, we hypothesized that induction chemotherapy (ICT) could be used in locally advanced (T3-T4) HPV+OPC to down-stage patients and make them eligible for de-escalation and simultaneously improve tumor hypoxia. Methods: We conducted a pilot study in HPV+ OPC patients with AJCC v7 T3-T4 and/or large volume N2b-N2c-N3 disease (i.e. pts ineligible for ROC Study (NCT03323563)). ICT – carboplatin (AUC2), paclitaxel (90 mg/m2), and cetuximab (250 mg/m2 after 400 mg/m2 loading dose) weekly for 6 weeks. To be eligible for de-escalation (ROC), after ICT, patients needed to be down-staged (<=T2). 18F-FMISO PET scan done prior to ICT, after ICT, and, if eligible for ROC study, about 2 weeks after start of radiation therapy. If an 18F-FMISO PET scan showed no hypoxia at any time point, no further scans necessary and patients received 30Gy of radiation therapy with 2 cycles of chemotherapy concurrently. Primary outcome is 2-year local control rate in 20 evaluable patients (description only in this pilot study). This abstract reports only on the outcomes of the ICT portion of the study. Results: 20 patients were accrued 3/2023-12/2023. Median age - 70 years old (46-88); Male – 95%; ECOG PS 0 – 80%. Tumor stage – T3 (70%); T4a (30%); N2b (70%); N2c (30%). All 20 patients had pretreatment hypoxia by 18F-FMISO. Of the 17 evaluable patients post ICT, 14 (82%) had no hypoxia on post ICT scan (other 3 still receiving ICT). Of 3 patients with hypoxia after ICT, 2 had resolution 2 weeks into radiotherapy, and 1 patient is still pending intra-treatment scan. All 17 evaluable patients had a significant enough of a response anatomically to allow treatment on the ROC Study. All patients to date were able to receive 2 cycles of cisplatin (100 mg/m2) without dose or treatment adjustment. Conclusions: Preliminary results suggest that ICT can allow more advanced tumors (T3/T4), that are typically excluded from de-escalation studies, to be de-escalated and may eliminate tumor hypoxia in a large proportion of cases, but a larger study is needed to confirm these results. Further followup of outcomes (2 year local control rate) is still needed. Clinical trial information: NCT05491512 .
Beyond the initial diagnosis: Epidemiological factors associated with second primary cancers among patients with head and neck squamous cell carcinoma (a SEER-based study).
Authors: Shah Anand , Gwalani Pranav , Gor Rajvi , GOR DHAIRYA , Sivanandam Abiram , Nehra Anupama Hooda
Published: June 2024

6081

Background: Patients with Head and Neck cancer squamous cell carcinoma (HNSSC) have an increased risk of developing a Second Primary Cancer (SPC). We evaluated the epidemiological factors associated with SPC among patients with Stage 1-4 HNSCC using the SEER database from 2004-2020. Methods: Stage 1-4 HNSSC cases from 2004-2020, with a minimum of six months of follow-up, were identified using SEER.Stat 8.4.2 using ICD-10 CM codes. Adjusted odd’s ratios (aOR) for developing SPC (dependent variable) and the independent variables (sex, age, race and ethnicity, site of primary cancer, and marital status) were generated using multivariate logistic regression. All the analyses were performed on SAS OnDemand. Results: 127,919 cases of HNSCC were identified from 2004-2020. Oral cavity cancer accounted for 41.2% of the cases. 18,192 (14.2%) patients developed SPC. Patients with primary hypopharynx, laryngeal, and oral cavity cancer had the highest odds of developing SPC (p< 0.0001). The most prevalent sites for developing SPC were the lung (25.0%), head and neck (24.1%), and prostate (10.6 %). Males had significantly higher odds of developing SPC than females (aOR - 1.11 (1.07, 1.5)). When compared to the NH-white population, Hispanics and NH-Asian had significantly lower odds of developing SPC (aOR - 0.72 (0.68, 0.77) and 0.72 (0.68, 0.78) respectively), while NH-Blacks had higher odds of developing SPC (aOR - 1.1(1.01,1.23)). Conclusions: Our study emphasizes the substantial risk of SPC in HNSCC patients, with oral cavity cancer as the predominant primary cancer subtype. Specific HNSCC sites show elevated SPC odds, mainly primary hypopharyngeal cancer, emphasizing the need for targeted surveillance. Demographic variations reveal gender and racial disparities in SPC susceptibility, advocating for tailored monitoring and preventive strategies in high-risk subpopulations to enhance overall cancer care and survivorship. [Table: see text]
MR radiomics and neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma.
Authors: Lu Xueguan , Zhou Xin , Gong Jing , Xu Tingting , Shen Chunying , Wang Yu , Hu Chaosu , Gu Yajia , Zhu Lin , Lv Wenjiao
Published: June 2024

6085

Background: In HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), patients with good response to neoadjuvant chemotherapy (NAC) exhibit superior prognosis. Accurate prediction of NAC response allows for NAC candidate selection and personalized treatment de-intensification in HPV-positive OPSCC. In this study, we aimed to apply baseline magnetic resonance (MR) radiomic features to predict NAC response and prognosis. Methods: Pre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Radiomic features of both oropharyngeal lesions and metastatic nodes were extracted on T2WI and contrast-enhanced T1WI sequence. Patients were divided into training cohort (n=47), prospective validation cohort (n=49) and real-world validation cohort (n=35). Following radiomic feature selection, a linear support vector machine (SVM) model was built and validated for NAC response prediction. Nomograms that combined radiomics and clinical characteristics were then developed to predict survival outcomes. The performance of response models was assessed by the area under the curve (AUC), accuracy, sensitivity, specificity and prognostic models were measured by C-index. RNA-seq and proteomic data were further leveraged and compared to interpret the molecular features underlying radiomic signatures with differential NAC response. Results: For NAC response prediction, the fusion model with both oropharyngeal and nodal radiomic signatures on multi-sequence MR images achieved encouraging performance to predict good responders in the training cohort (AUC 0.89, 95% CI, 0.79-0.95) and prospective validation cohort (AUC 0.71, 95% CI, 0.59-0.83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients in training cohort and two validation cohorts (PFS, C-index: 0.85, 0.76 and 0.83; OS, C-index: 0.79, 0.76 and 0.87). An exploratory analysis in the prospective validation cohort showed that de-intensified radiotherapy after NAC in low-risk patients yielded 100% in both PFS and OS. Furthermore, expression analysis unveiled distinct molecular phenotypes in relation to NAC response, where poor responders had predominantly enhanced keratinization while good responders were featured by stronger innate and adaptive immune response. Conclusions: The MR-based radiomic models and subsequent prognostic models efficiently discriminate among patients with different NAC response and survival risk. This study provides a new strategy for patient selection in HPV-positive OPSCC that are suitable for personalized de-intensification. Integration of radiomics in future trials is warranted.
Clinical and genomic characterization of sporadic medullary thyroid carcinoma in Chinese patients.
Authors: Liu Yang , Lu Tingwei , Lin Xiaoyan
Published: June 2024

6094

Background: Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. MTC has a low prevalence and a relatively worse prognosis compared with differentiated thyroid carcinoma. About 75% of all MTCs are sporadic. The clinicogenomic landscape of sporadic medullary thyroid carcinoma (sMTC) in the Chinese population was rarely described. Methods: Formalin-fixed paraffin-embedded (FFPE) samples and/or tumor tissues from a total of 121 sMTC patients from 22 centers were retrospectively collected and tested using a targeted 28-gene next-generation sequencing (NGS) panel (May 2022 to November 2023). Clinicopathological data, including age, gender, histological diagnoses, site, tumor size, and status of the lymph nodes and distant metastasis were reviewed. Regression analyses were performed to examine the association between the clinicogenomic characterization and pathologic features. Results: A total of 105 out of 121 sMTC were NGS-positive. The mutant genes included RET(66.9%), RAS(20.7%), BRAF(1.6%), TSHR(0.8%). The top 5 frequent mutations were RET M918T (24.8%, 30/121), HRAS Q61R (8.3%, 10/121), RET C634R (7.4%, 9/121), RET V804M (4.1%, 5/121), HRAS Q61K (4.1%, 5/121). Of the 13 co-mutations, 12 were RET mutations or co-occurrence of RET with other genetic alterations. Besides, the higher the age, the lower the probability of lymph node metastasis (OR=0.95, p=0.005). Also, patients with common RET mutations (including M918T, C634, C630, C611, C618, C620, A883F, S891 and V804) tended to have lymph node metastases (OR=5.67, p=0.016). We observed a significant positive linear relationship (Beta=2.0) between other gene mutations (non-RET mutations and non-RAS mutations) and tumor size. However, when the tumor diameter was analyzed according to whether it was greater than 1cm, we found that clinical factors such as age, sex, and gene mutation were not related to tumor size. Moreover, we did not find any association between this cutoff value of tumor size and lymph node metastases. It indicated that sMTC clinical diagnosis and treatment may consider pathologic and genomic features, not just whether the tumor size is >1cm. Conclusions: Our study first provided the molecular characteristic of Chinese patients with large-scale sMTC. Analysis revealed that common RET mutations may be potential predictors of lymph node metastases. These conclusions remain to be validated in prospective large-scale cohorts.
Secondary myeloid malignancy after CAR T cell therapy for non-Hodgkin lymphoma (NHL).
Authors: Habib Alma , Welkie Rina , Butman Jacob , Silberman Pedro C , Forero Jose Vicente , Sawalha Yazeed , Christian Beth , Maddocks Kami J. , Epperla Narendranath , Jaglowski Samantha Mary , Bond David Alan , Choe Hannah Kyung , Brammer Jonathan Edward , Kittai Adam , Bezerra Evandro , Voorhees Timothy , Vasu Sumithira , Wall Sarah Allison , De Lima Marcos J.G. , Denlinger Nathan
Published: June 2024

7033

Background: Prior studies have described toxicities associated with chimeric antigen receptor T cell therapy (CART). Recently, myeloid malignancies were identified in myeloma patients (pt) after receipt of cilta-cel. In this study, we sought to describe the cumulative incidence and characteristics of secondary myeloid malignancies in pt treated with CART for NHL. Methods: We conducted a single institution retrospective study among pt ages ≥18 years (yr) who received commercial CART for NHL at Ohio State between December 2017 to April 2022. Descriptive statistics were used to summarize pt/disease characteristics. Cumulative incidence was calculated from date of infusion with death/relapse as competing risks. Results: For 190 pt treated with CART, median age was 63 yr (23-85 yr). Disease subtypes included diffuse large B-cell lymphoma (BCL)/high grade BCL, Richter transformation, and mantle cell lymphoma (79.5%, 8.4%, and 7.4%). Products included tisa-cel (47.9%), axi-cel (43.1%), brexu-cel (7.4%), and liso-cel (1.6%). Grade 3-4 neutropenia developed in 29% and 18% of pt at 30 days and 90 days post-CART. Median follow-up was 17 mo (0.5-63 mo). 48% were alive at time of analysis. Myeloid malignancy post-CART occurred in 7 pt with a median time to development of 29 mo (18-41 mo). Characteristics (Table) included complex karyotype, TP53 and chromosome 5/7 abnormalities. Cumulative incidence of secondary malignancy was 1%, 5%, and 6% at 2, 3, and 4 yr post-CART. Conclusions: We report on incidence of secondary myeloid malignancy in pt receiving CART for NHL. Mutational characteristics of secondary malignancies were those classically associated with therapy-related myeloid malignancy, thus presumed to be associated with prior exposure to chemotherapy (eg. alkylators/VP-16). Further investigation in larger cohorts with additional observation time, to allow for appropriate risk discussion, is required. [Table: see text]