tbuckley/cabot-search huggingface dataset:
Molecular analysis of surgical margins with NGS to assess microscopic residual disease in early oral squamous cell carcinomas.
Authors: Antoine Moya-Plana, Damien Vasseur, Anne Auperin, Thibault Dayris, Ludovic Lacroix, Stephane Temam
Journal: Journal of Clinical Oncology (2024)

6063 Background: The prognosis of early oral squamous cell carcinomas (OSCC) is strongly correlated with local disease control. However, patients with T1-T2 OSCC operated with clear margins have a 5-year local relapse rate of 10 to 15%. An accurate evaluation of the microscopic residual disease (MRD) is therefore essential. Interestingly, innovative techniques have recently been developed to detect circulating tumor DNA. Methods: A prospective multicenter trial based on patients with T1-T2 OSCC treated surgically with clear margins, was designed to assess the feasibility of a molecular analysis (tetranucleotide instability) of these margins to evaluate a potential MRD while adapting the postoperative strategy (NCT00232960). We, then, evaluate the feasibility of detecting MRD in the margins by identifying specific molecular abnormalities in the primary tumor with Whole Exome Sequencing (WES) and explore them in margins with deep target NGS panel (TGS) and digital PCR (dPCR) for hotspot mutations. Results: 310 patients were included initially with 216 tumor/margins samples available for molecular analysis. After a standard pathologic analysis, all surgical margins were negative.Median follow-up was 58 months [30;83]. Tumor was informative for tetranucleotide instability analysis in 63% of cases. Positive molecular margins were observed in 17.3% of cases, leading to a postoperative treatment (surgery or radiotherapy). In informative tumors, molecularly driven treatment seemed to lower the 5-year local recurrence rate from 14.1% to 6.4% (p=0.15). Among this initial cohort, 108 primary tumors were secondarily screened by WES to find mutations of interest, with an informativity rate of 75%. Positive molecular results (TGS or dPCR), with at least one positive margin, were observed in 19.4% of patients. Then, analyzing retrospectively the oncologic outcomes, we observed a significant benefit for local control at 5 years for patients with TGS-dPCR negative results in all margins compared to pathologic negative margins (91.7% versus 64.1%, p=0.02). Conclusions: To our knowledge, this is the first report of local MRD assessment after surgery using NGS.Molecular analysis of resection margins for early OSCC lead to a better evaluation of MRD and personalized postoperative decision making to improve local control. Clinical trial information: NCT00232960 .
Relationship between infiltration of tissue-resident memory T cells (TRM) in head and neck squamous cell carcinoma (HNSCC) tissue and localization and age.
Authors: Adrian von Witzleben, Matthew Ellis, Gareth Thomas, Thomas K Hoffmann, Simon Laban, Christian H.H Ottensmeier
Journal: Journal of Clinical Oncology (2024)

6089 Background: Elevated levels of tumor-infiltrating lymphocytes (TILs) have been correlated with improved survival rates in cancer patients. Among TIL subgroups, tissue-resident memory T cells (TRM, CD8+CD103+) are recognized as pivotal contributors to the anti-cancer immune response. In this study, we aimed to evaluate TRM presence in Head and Neck Squamous Cell Carcinoma (HNSCC) tissue utilizing a developed tissue microarray (TMA) and a multiplex immunohistochemistry (MxIHC) approach. Methods: HNSCC cases from Southampton Hospital spanning the years 2000 to 2016 were reviewed, resulting in the identification of approximately 300 cases with sufficient primary tumor material. A TMA was constructed by triplicate coring of marked tumor areas on all slides. Subsequently, MxIHC, incorporating markers such as CD8 and CD103, was performed using a stain-scan-strip methodology. Digital image analysis software was employed to analyze scanned slides, and a quality check (QC) was conducted. Results: Following QC, 193 primary tumors remained (hypopharynx and larynx: n = 28, lip and oral cavity: n = 51, oropharynx: n = 114). Significantly higher counts of CD8 T cells and TRM were observed in the combined group of oropharynx, lip and oral cavity compared to the combined group of larynx and hypopharynx. This significance persisted even after excluding HPV negative oropharynx cases. HNSCC of the lip and oral cavity itself had statistically more TRM than larynx and hypopharynx. No differences were found in the subgroups between tonsil and tongue base. Stratifying the analysis by age revealed a statistically significant increase in TRM infiltration in HNSCC among young patients (≤50 years) compared to the 51-60 years and 61-70 years age groups, a pattern not observed for CD8 alone. Conclusions: This study underscores the importance of HNSCC heterogeneity and highlights the impact of age on immune infiltration, emphasizing the unique contribution of TRM in the anti-cancer immune response.
Validation of a prognostic nomogram for locally advanced oropharyngeal carcinoma (OPC) treated with intensity modulated radiation therapy (IMRT) ± systemic therapy (ST).
Authors: Paolo Bossi, Riccardo Gili, Stefano Calza, Lisa F. Licitra, Marta Maddalo, Almalina Bacigalupo, Liliana Belgioia, Jon Cacicedo, Nadia Facchinetti, Almudena Garcia, Marc Oliva, Pierluigi Bonomo, Giuseppe Sanguineti, Pierfrancesco Franco, Athanassios Argiris, Amanda Psyrri, Ester Orlandi
Journal: Journal of Clinical Oncology (2024)

6088 Background: The interplay among prognosticators in OPC patients (pts) may be influenced by sociodemographic, geographic, epidemiologic and genetic features. We aimed to validate an existing prognostic nomogram (PN) (Fakhry et al 2017) in a large, independent, geographically homogeneous pt cohort. Methods: We retrospectively collected data on consecutive OPC pts treated with definitive IMRT (66-72 Gy) ± systemic therapy (ST) in 14 South-European Centres from 2007 to 2019. We analysed the role of the nomogram prognostic factors (PF) (T and N stage, age, p16 status, smoking, performance status, weight loss, anemia, education, and marital status) with respect to overall survival (OS) and progression-free survival (PFS), and we also evaluated alcohol abuse, comorbidities according to ACE-27 and the presence of a caregiver as added PF. The PN was evaluated in terms of discrimination performance (Harrel C-index) and calibration (ratio O/E and calibration line). Model was recalibrated evaluated via optimism adjusted C-index. Results: We considered 786 pts, with a median follow-up of 63 months (0-189). The table reports pts characteristics. The PN showed a good discrimination for OS and PFS both at 2- and 5-years, not dissimilar from original external validation, with a C-index of 0.75 (CI 95% 0.70-0.79,) and 0.68 (0.64-0.72), respectively. Adding alcohol abuse, comorbidities and caregiver presence did not change the PN. Regarding OS, the model estimated risk was slightly higher than the observed, with an O/E ratio of 0.73 (CI 95% 0.57-0.93) and 0.60 (0.49-0.74) at 2- and 5- years and calibration slope of 1.07 (0.83-1.31). For PFS, the O/E ratio was 0.48 (0.40-0.58) at 2 years and 0.50 (0.42-0.58) at 5 years, and a calibration slope of 0.89 (0.66-1.12). Both for OS and PFS rescaling of baseline hazard and model coefficients resulted in a better calibrated model. Model was validated also after missing data imputation, via MCE (m=5) showing consistent estimates. Conclusions: We validated the prognostic nomogram developed by Fakhry et al. in a large independent European cohort, demonstrating its applicability. These real-life data may represent the benchmark for the design of new prospective clinical trials.[Table: see text]
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: Anand Shah, Pranav Gwalani, Rajvi Gor, DHAIRYA GOR, Abiram Sivanandam, Anupama Hooda Nehra
Journal: Journal of Clinical Oncology (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&lt; 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]
Prevalence of Chronic Kidney Disease in Type 1 Diabetes Among Adults in the U.S.
Authors: Peter Rossing, Per-Henrik Groop, Rakesh Singh, Robert Lawatscheck, Katherine R. Tuttle
Journal: Diabetes Care (2024)

The prevalence of chronic kidney disease (CKD) in adults ≥18 years of age with type 1 diabetes in the U.S. was determined using National Health and Nutrition Examination Survey (NHANES) data.
Can TTMV clearance predict recurrence in HPV HNSCC?
Authors: Krzysztof Misiukiewicz, Leslie Anne Worona, Emily J Ramos, Richard Lorne Bakst, Kunal K. Sindhu, William Westra, Scott Roof, Eric Michael Genden, Marshall R. Posner
Journal: Journal of Clinical Oncology (2024)

6066 Background: Patients with locally advanced (LA) HPV HNSCC are treated with various types of induction chemotherapy (IC) followed by standard (sd) or reduced (rd) chemoradiation (CRT). Tumor tissue-modified viral HPV DNA (TTMV) pairs with PET-CT in predicting an early detection of treatment failure in HPV-related HNSCC. Mid-treatment TTMV assessment in HPV-related HNSCC can help identify patients who are eligible to receive a lower dose of IC and/or CRT or those who may require close follow-up. Methods: Patients with LA HPV+ HNSCC with high-risk features (radiographic ECE, T4 primary, &gt;N2c) and &lt;20 pack-year (py) smoking history were treated with IC followed by rdCRT (56 Gy); sdCRT (70 Gy) was used in non-responders. 16/23 received IC with TPF, 1/23 TP, and 6/23 TP-PD1, and all patients received carboplatin weekly with their CRT. Regeneron trial patients who received TP-Cemiplimab (PD1) IC followed by sdCRT are also continuing adjuvant Cemiplimab alone for 6 months (NCT05376553). PET-CT-confirmed residual, recurrent, or metastatic diseases were defined as treatment failures; TTMV + patients only if PET-CT confirmed. Results: 23 subjects treated with IC followed by CRT between 2/4/21-1/26/24, who had pre- and post-treatment TTMV were included in our analysis. The median pre-IC TTMV was 8082 (27 – 90770). The median follow-up time from treatment start was 21 months. 9/23 patients had full clearance TTMV after 1 cycle of IC defined as rapid responders (RR). 11/23 patients still had positive TTMV after 1 st cycle of IC were defined as slow responders (SR). 1 patient had no TTMV done after 1 cycle of IC but was elevated after 2 nd IC; he was defined as SR. 2 patients had a positive pre-IC TTMV, but no TTMV was drawn during IC to see if RR. 1 of 2 patients was TTMV negative prior to CRT, and 2/2 had a 1 st post IC negative TTMV done 1 week after CRT started. They were both included in the analysis but defined as unknown response status. TTMV testing was done for all 23 subjects after CRT; all were negative. All subjects have TTMV testing done during their surveillance visits. Among 9/23 RR, none developed a failure. Among 12/23 SR, 3 patients developed a failure: 1/3 was TTMV+ but PET-, being followed with TTMV and PET-CT; and 2/3 were confirmed failures, TTMV+ and PET+; 1 locoregional, 1 metastatic. 2 patients were not known to be a SR or RR and had no recurrence. Among 23 patients, NPV of TTMV to detect failure was 100%, but PPV was 96% (1/23). Conclusions: IC followed in rapid clearance of TTMV in 39% of patients, and all remained disease-free. 3/11 (27%) with persistently elevated TTMV after cycle 1 relapsed as of this time point. This small study was not large enough to be practice-changing. However, this is significantly hypothesis-generating and should be tested in a larger trial to help identify patients for de-escalation (RR) or closer surveillance (SR).
Induction chemotherapy followed by concurrent chemoradiotherapy combined with toripalimab and Endostar in high-risk locally advanced nasopharyngeal carcinoma: A multicenter, randomized, phase 2 trial.
Authors: Min Kang, Kunyu Yang, Ying Lu, Jinming Yu, Daiyuan Ma, Shuang Tang, Jianquan Gao, Tingting Zhang, Zhendong Yang, Jun Lv, Yutao Qin, Fang Wu, Lin Ruan, Kang Liu, Huan Dong, Zhen Meng, Yating Qin, Rensheng Wang
Journal: Journal of Clinical Oncology (2024)

6086 Background: Even though induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) can improve the survival rate of patients with locally advanced nasopharyngeal carcinoma (LA-NPC), the recurrence and/or metastasis rates for patients with stage IV (T4 and/or N3) diseases remain high. This study investigates the efficacy and safety of adding Toripalimab (PD-1 inhibitor) and Endostar (recombinant human endostatin) to IC-CCRT in patients with high-risk LA-NPC. Methods: High-risk LA-NPC patients were randomly divided (1:1) into either the IC-CCRT+TE group (gemcitabine and cisplatin induction chemotherapy followed by concurrent chemoradiotherapy combined with Toripalimab and Endostar) or the IC-CCRT group (gemcitabine and cisplatin induction chemotherapy followed by concurrent chemoradiotherapy). Toripalimab (240mg, d1) was administered intravenously every 3 weeks for up to 12 cycles (3 induction, 2 concurrent, and 7 adjuvant). Endostar (7.5mg/m2, d1-10) was continuously injected intravenously every 3 weeks for a total of 5 cycles (3 induction and 2 concurrent). The primary endpoint was 3-year progression-free survival (PFS), and the secondary endpoints included 3-year overall survival (OS), 3-year locoregional relapse-free survival (LRFS), 3-year distant metastasis-free survival (DMFS), objective response rate (ORR) and safety. Results: From September 7, 2020, to August 23, 2022, a total of 106 eligible patients were randomly assigned to the IC-CCRT+TE group (n = 53) and IC-CCRT group (n = 53). At a median follow-up of 25 months, the PFS was significantly improved in the IC-CCRT+TE group compared to the IC-CCRT group (HR=0.36, p=0.041). 28 patients (52.8%) in the IC-CCRT+TE group and 5 patients (9.4%) in the IC-CCRT group achieved complete response (CR) after induction chemotherapy, and the difference was statistically significant (P &lt; 0.001). The incidence of grade ≥3 acute adverse events in the IC-CCRT+TE group and IC-CCRT group was 66.0% and 62.3%, respectively. The incidence of grade ≥3 late adverse events in two groups was 5.8% and 5.7%, respectively. The incidence of grade ≥3 immune-related adverse events was only 4.7%. Conclusions: IC-CCRT combined with Toripalimab and Endostar significantly improved PFS in patients with high-risk locally advanced nasopharyngeal carcinoma, and the adverse events are manageable. Clinical trial information: NCT04447326 .
PARP-1 selectively impairs<i>KRAS</i>-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma
Authors: Friederike L Keggenhoff, Darko Castven, Diana Becker, Stojan Stojkovic, Jovana Castven, Carolin Zimpel, Beate K Straub, Tiemo Gerber, Harald Langer, Patricia Hähnel, Thomas Kindler, Jörg Fahrer, Colm J O'Rourke, Ursula Ehmer, Anna Saborowski, Lichun Ma, Xin Wei Wang, Timo Gaiser, Matthias S Matter, Christian Sina, Stefanie Derer, Ju-Seog Lee, Stephanie Roessler, Bernd Kaina, Jesper B Andersen, Peter R Galle, Jens U Marquardt
Journal: Gut (2024)

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options.
Development and validation of an assay to quantify plasma cell-free human papillomavirus DNA for 13 high-risk types that cause 98% of HPV-positive cancers.
Authors: Michael Wotman, Weihong Xiao, Robyn Du, Bo Jiang, Suyu Liu, Maura L. Gillison
Journal: Journal of Clinical Oncology (2024)

6065 Background: Plasma cell-free HPV DNA (cfHPV) may be a valuable tool for identification of patients with local-regionally advanced HPV-positive cancers at risk for recurrence after chemoradiation. Technical validation is required for use as an integral biomarker in a prospective clinical trial. Methods: Cell-Free 13 (i.e., CF13) is a digital-droplet PCR assay for quantification of 13 high-risk HPV types and control ERV3 in plasma that considered both variant sequences into primer/probe design and a distance matrix in phylogenetic analysis in multiplex combinations. Oligonucleotides/plasmids encoding type-specific E6/E7 regions were used as positive controls. Limit of blank, detection, quantification (LoB, LoD, LoQ), linear range, inter- and intra-assay coefficients of variation (CoV), and type-specific cross-reactivity were determined as were sensitivity and specificity for an HPV-positive diagnosis in a cohort of 278 oropharyngeal/unknown primary/oral cavity cancers tested for HPV by E6/E7 mRNA qRT-PCR or p16 IHC and HPV in situ hybridization. Results: Under identical assay conditions, the LoB, LoD and linear range were &lt;1, 5 and 5 to 200,000 virus copies without HPV type-specific cross-reactivity. Multiplexing had no effect on LoD or linearity. LoQ was 16 copies/ml plasma for all 13 HPV types. For 80 and 10,000 copies per ml, inter-assay CoV ranged from ~15-28% and ~3.2-4.6% and intra-assay CoV ranged from ~16-38% and 0.2-3.3%, respectively. cfDNA purification method (manual v automated; extraction efficiency 142% and 91% for 16 and 10,000 HPV16 copies/ml), input plasma volume (1, 2, or 4 ml), total background cfDNA (&lt;1800ng) or genomic DNA (&lt;700ng) did not affect quantification. For a diagnosis of HPV-positive cancer, sensitivity and specificity were 91.1% (214/235) and 97.7% (42/43), respectively. cfHPV was associated with gender, race, T stage, N stage, and primary treatment modality. When compared to below the median (≤230 copies/ml), cfHPV above the median was associated with worse progression-free survival (HR=2.26, 95% CI 1.23-4.17, p=0.009) in univariate analysis. However, this was no longer significant after adjustment for age, T stage, and M stage (HR adj =1.78, 95% CI 0.95-3.35, p=0.07). Conclusions: CF13 has high sensitivity, accuracy, precision, linearity, HPV type-specificity, and robustness, offering a rigorously validated assay applicable to ~98% of patients with HPV-positive cancer. CF13 had excellent clinical sensitivity and specificity for a diagnosis of HPV-positive OPC.
Perimarginal lymph node metastasis in gingivo-buccal complex carcinoma: Is it time to push the limits of neck dissection?.
Authors: Sandipta Mitra, Smriti Panda, Aanchal Kakkar, Kapil Sikka, Alok Thakar, Amit Chirom Singh, Rajeev Kumar
Journal: Journal of Clinical Oncology (2024)

6069 Background: Perimarginal nodes (PMN) are a group of perifacial lymph nodes that lie in close relationship with marginal mandibular nerve (MMN). They lie in the lymphatic drainage pathway of gingivo-buccal cancers (GBC), above the lower border of mandible which forms the superior limit of conventional neck dissection and thus remain unaddressed. With reported incidence of metastasis as high as 20.5%, we aimed to explore incidence of PMN metastasis in GBC, its correlation with histopathological tumor and nodal characteristics. Methods: A prospective study was conducted on 112 consecutive treatment naïve patients of GB squamous cell carcinoma. Patients with unresectable nodal disease, distant metastasis and prior radiotherapy or surgery to neck were excluded. PMN dissection was performed in the quadrangle bounded superiorly by the mandibular alveolar ridge, inferiorly by lower border of mandible, anteriorly by mental foramen and posteriorly by anterior border of masseter. On histopathological analysis, serial step sectioning and cytokeratin immunohistochemistry were performed. Prospective clinical characteristics analyzed were subsite, clinical tumor, nodal stage, location of primary and clinical skin involvement. PMN positivity was correlated with demographic, clinical, nodal status. Histopathological characteristics analyzed included tumor grade, pathological tumor, nodal stage, tumor size, skin and/or bone involvement, depth of invasion, Brandwein Gensler histological risk score and lympho-vascular emboli. MMN functional outcome was graded according to House-Brackman (HB) grading recorded at 3 and 6 months post-operatively. Results: Baseline characteristics are summarized in the table. The PMN were identified histologically in 75.89% (85/112) patients. Metastasis in these nodes were identified in 15.2% (17/112) patients. Our study revealed an occult PMN metastasis of 16.67% (13/78). None of the pre-operative clinical factors was found to be significant in predicting incidence of metastasis. Higher nodal burden (p=0.01) and pathological skin involvement (p=0.03) had statistically significant odds of having PMN metastasis on multivariable analysis. At 6 months follow-up, none of the patients had any MMN functional deformity at rest. Conclusions: There is a high incidence of occult PMN metastasis from gingivo-buccal complex cancer. High nodal stage and pathological skin involvement are independent adverse prognostic factors for PMN metastasis. The limits of conventional neck dissection should be expanded to include clearance of PMN in all cases of gingivo-buccal cancers. [Table: see text]