bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.