tbuckley/cabot-search huggingface dataset:
Kidney Volume and Risk of Incident Kidney Outcomes
Authors: Jianhan Wu, Yifan Wang, Caitlyn Vlasschaert, Ricky Lali, James Feiner, Pukhraj Gaheer, Serena Yang, Nicolas Perrot, Michael Chong, Guillaume Paré, Matthew B. Lanktree
Journal: Journal of the American Society of Nephrology (2024)

Key Points Low kidney volume was a risk factor of incident CKD. A nonlinear relationship existed whereby individuals in the bottom tenth percentile of kidney volume exhibited exaggerated risk of CKD and albuminuria. Kidney volume could improve the classification of kidney disease risk. Background Low total kidney volume (TKV) is a risk factor of CKD. However, evaluations of nonlinear relationships, incident events, causal inference, and prognostic utility beyond traditional biomarkers are lacking. Methods TKV, height-adjusted TKV, and body surface area–adjusted TKV of 34,595 White British ancestry participants were derived from the UK Biobank. Association with incident CKD, AKI, and cardiovascular events were assessed with Cox proportional hazard models. Prognostic thresholds for CKD risk stratification were identified using a modified Mazumdar method with bootstrap resampling. Two-sample Mendelian randomization was performed to assess the bidirectional association of genetically predicted TKV with kidney and cardiovascular traits. Results Adjusted for eGFR and albuminuria, a lower TKV of 10 ml was associated with a 6% higher risk of incident CKD (hazard ratio, 1.06; 95% confidence interval [CI], 1.03 to 1.08; P = 5.8×10 −6 ) in contrast to no association with incident AKI (hazard ratio, 1.00; 95% CI, 0.98 to 1.02; P = 0.66). Comparison of nested models demonstrated improved accuracy over the Chronic Kidney Disease Prognosis Consortium Incident CKD Risk Score with the addition of body surface area–adjusted TKV or prognostic thresholds at 119 (tenth percentile) and 145 ml/m 2 (50th percentile). In Mendelian randomization, a lower genetically predicted TKV by 10 ml was associated with 10% higher CKD risk (odds ratio, 1.10; 95% CI, 1.06 to 1.14; P = 1.3×10 −7 ). Reciprocally, an elevated risk of genetically predicted CKD by two-fold was associated with a lower TKV by 7.88 ml (95% CI, −9.81 to −5.95; P = 1.2×10 −15 ). There were no significant observational or Mendelian randomization associations of TKV with cardiovascular complications. Conclusions Kidney volume was associated with incident CKD independent of traditional risk factors, including baseline eGFR and albuminuria. Mendelian randomization demonstrated a bidirectional relationship between kidney volume and CKD.
The potential prognostic value of the head and neck advanced lung inflammation index (HN-ALI) for patients treated with immunotherapy.
Authors: Daria Maria Filippini, Francesca Carosi, Matteo Fermi, Lucia Trudu, Eleonora Cabitza, Martina Napolitano, Roberta Depenni, Elisabetta Nobili, Massimo Dominici, Gabriele Molteni, Federica Bertolini
Journal: Journal of Clinical Oncology (2024)

6052 Background: The ALI is recognized as a potential prognostic and predictive biomarker for patients (pts) treated with immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer. In head and neck squamous cell carcinoma (HNSCC) its prognostic role has been acknowledged in locally advanced setting. We evaluated whether HN-ALI could provide similar value in pts with recurrent/metastatic (R/M) HNSCC undergoing treatment with ICIs. Methods: We conducted a multicentric observational retrospective study including R/M HNSCC pts treated with ICIs alone or in combination with chemotherapy from April 2016 to November 2023. The ALI was calculated as follows: BMI (kg/m 2 ) × serum albumin (g/dL)/neutrophil-to-lymphocyte ratio (NLR). Using the bibliographic cut off value of 18, pts were divided into two groups: ALI &lt; 18 (high inflammation) and ALI &gt; 18 (low inflammation). The primary outcomes were overall survival (OS) and progression free survival (PFS), evaluated with the Kaplan-Meier estimator. Cox proportional hazard regression models were employed to perform multivariate analysis. Results: A total of 145 pts [105 males, median (m) age 66 years, 128 with ECOG PS &lt; 1] were treated with ICIs (35% nivolumab, 64% pembrolizumab) across two Italian centers. Primary tumor sites were: oral cavity (35%), oropharynx (33%), larynx (14%), hypopharynx (7%), other (9%). ICIs were administered as single agents in 86 pts and in combination with chemotherapy in 59 pts. The HN-ALI was collected for 92 pts. The mPFS was 6 months (95%CI, 2.16-9.83) within the ALI group &gt; 18 versus 1 month for the ALI group &lt; 18 (95%CI, 0.26-1.73) (p&lt; .001); analogously, the mOS was 17 months (95%CI, 11.63-22.36) versus 2 months (95%CI, 0.68-3.32) for the ALI group &gt; 18 and &lt; 18, respectively (p&lt; .001). At the multivariate analysis, high ALI score represented an independent risk factor for better OS, also including ECOG PS and PD-L1 expression [HR 0.38; (95% CI,0.15 – 0.96), p= .042], while showing a trend towards longer disease progression [HR 0.52; (95% CI, 0.26 - 1.02), p= .058]. Conclusions: In our experience, ALI value &gt;18 is associated with better prognosis in pts treated with ICIs alone and in combination with chemotherapy. Further analyses are warranted to validate the prognostic relevance of the ALI value in pts with HNSCC undergoing ICIs.
Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.
Authors: Lydia D. Chow, Robert Hsu, Jorge J. Nieva, Rebecca Umayam, Angela Smith Bryant, Denice Tsao-Wei, Ming Hsieh, Ray Yin, Anthony B. El-Khoueiry, Jacob Stephen Thomas
Journal: Journal of Clinical Oncology (2024)

6042 Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m 2 and 160mg/m 2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and &lt; 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in &gt;1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced &gt; grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .
Real world effectiveness and safety of low dose nivolumab with metronomic chemotherapy in patients with advanced platinum-resistant head and neck cancer: An Indian institutional experience.
Authors: Shruti Kate, Richa Sharma, Rajnish Vasant Nagarkar, Ankita Dadabhai Shirsath, Mukesh Choudhary, Roshan Patil
Journal: Journal of Clinical Oncology (2024)

6050 Background: Triple Metronomic chemotherapy (TMC) regimen of low-dose methotrexate, erlotinib, and celecoxib has been proven to improve overall survival (OS) of advanced platinum-resistant head and neck cancer (HNC) patients. The addition of low-dose nivolumab to metronomic chemotherapy is an alternative standard of care for those patients, who cannot access full-dose checkpoint inhibitors. In the present study, we aimed to assess the real world effectiveness and safety of low-dose nivolumab along with TMC. Methods: We performed a prospective analysis of advanced platinum-resistant HNC patients treated at our institute from June 2021 to June 2023 with TMC and low-dose immunotherapy consisting of capsule celecoxib (200 mg twice daily), tablet methotrexate (9 mg/m 2 /week), and erlotinib (150 mg once daily), along with intravenous nivolumab 20 mg (once every 2 weeks). Data was analysed descriptively and the Kaplan-Meier method was used to estimate OS, progression-free survival (PFS), and duration of response (DOR). Results: Overall, 85 patients of advanced platinum-resistant HNC were enrolled in this study. The median age of the patients was 54 years with male predominance. The most common primary sites were buccal mucosa (54%) and tongue (32%). The median follow-up was 6.5 months with 5 months of DOR to therapy. Median number of nivolumab doses received were 8 (IQR 2–48). The termination of therapy in the majority of patients was due to disease progression (55%). Most common adverse events reported were acneiform rash (62%), mucositis (52%), and fatigue (34%). Dose reduction for triple metronomic chemotherapy was required in 42% of patients for grade 3 and above adverse events. No grade 3/4 immune-related adverse events were reported throughout the study period. The median PFS and OS of the study population were observed to be 4.3 months and 8.8 months, respectively. Overall, 8 of 85 patients survived for ≥30 months and 20 (24%) patients were on treatment at the time of data analysis. Conclusions: Low-dose immunotherapy along with triple metronomic chemotherapy is a safe treatment option in real world advanced platinum-resistant HNC patients with acceptable outcomes.
Associations of ctDNA clearance and pathological response after neoadjuvant treatment in patients with locally advanced oral cancer.
Authors: Lai-ping Zhong, Zhi-hang Zhou, Ying-ying Huang, Yi-yi Zhang, Yi Lu, Bing Li, Jing Wang, Tong-chao Zhao, Wu-tong Ju, Dong-wang Zhu
Journal: Journal of Clinical Oncology (2024)

6043 Background: Neoadjuvant treatment (NAT) has improved clinical outcomes in some patients with locally advanced oral squamous cell carcinoma (LAOSCC). Effective biomarkers assessing the treatment response is still lacking. Previous studies have posed the potential of circulating tumor DNA (ctDNA) in monitoring treatment response, but the underlying mechanisms behind non-shedding in tumors remain unclear. Methods: 29 LAOSCC patients received NAT followed by surgery were enrolled. Seven (24.1%), 9 (31%), and 13 (44.8%) patients received NAT of apatinib+camrelizumab, TPF chemoagents, and toripalimab+paclitaxel+cisplatin, respectively. Tumor tissues before NAT underwent whole exome sequencing and whole transcriptome resequencing. Blood samples at pre-NAT (T0), mid-NAT (T1), before surgery (T2) and after surgery (T3) were analyzed using a tumor-informed, personalized NGS assay. Multi-omics analysis, including ctDNA status, was performed with patients' clinical features and outcomes. Results: Among the 29 patients received NAT, the MPR rate was 55.2% (16/29), and the pCR rate was 27.6% (8/29). At baseline(T0), ctDNA was detectable in 25/29 (86.2%) patients, which decreased over time (T1: 77.8%; T2: 51.7%; T3: 6.9%). Persistent ctDNA at T2 indicates a higher rate of residual disease after NAT (100% non-pCR) compared to ctDNA-negative patients (42.8% non-pCR; p = 0.0047). All patients achieving pCR at T2 were ctDNA-negative (n=8, 100%) including 2 non-shedders. The PPV and NPV for predicting pCR by ctDNA clearance at T2 were 57.1% (8/14) and 100% (15/15), respectively. ARSF, CFAP47, or HAUS8 mutations at baseline were associated with significantly higher pCR rates (p&lt;0.05). Four non-shedders with undetectable ctDNA at T0 were significantly enriched in patients with negative lymph nodes, lower clinical T stage, and high CPS score. The non-shedders had significantly lower tumor mutational burden (TMB), higher stromal score and cancer-associated fibroblast (CAF) (p&lt;0.05). Spatial transcriptome analysis further supports that MHC-II pathway-related genes were significantly up-regulated in the non-shedders. The enhancing communication intensity between CAFs, endothelial cells and T cells might provide an anti-cancer immune microenvironment for non-shedders. Conclusions: Our results indicate that the clearance of ctDNA clearance at T2 was associated with an improved pCR rate. Furthermore, our findings shed light on the factors that prevent ctDNA release from oral squamous cell carcinoma.[Table: see text]
Genomic characteristics of exceptional responders to treatment with PD-1 inhibitors in refractory/metastatic head and neck squamous cell carcinoma.
Authors: Mark Chang, Alexander Song, Logan James Deyo, Daniel Stamos, Chance H. Bloomer, Lara M. Khoury, Mercedes Porosnicu
Journal: Journal of Clinical Oncology (2024)

6062 Background: With the emergence of immune checkpoint inhibitors (ICIs), there are patients with advanced cancers experiencing exceptional treatment response with overall low treatment-associated toxicities. Despite success in refractory/metastatic head and neck squamous cell carcinoma (HNSCC), only a portion of patients experience benefit from the treatment with ICIs. Critical information on predictors of patient’s response to treatment is limited. At our institution we analyzed the genomic profiles of 36 patients with advanced HNSCC who demonstrated an exceptional response to treatment with PD-1 inhibitors. Methods: We reviewed patients with histologically confirmed HNSCC that had been treated with PD-1 inhibitors at Atrium Health Wake Forest Baptist Health. Treatment regimen included pembrolizumab 200mg every 3 weeks or nivolumab 240mg every 2 weeks. Response to therapy and duration of remission were monitored via CT scans and/or MRI scans at 3-month intervals, using RECIST 1.1 criteria. Exceptional responders were defined as achieving complete response (CR) or partial response (PR) for greater than six months, or stable disease (SD) for greater than one year. Progression free survival (PFS) and overall survival (OS) were measured from the date of PD-1 inhibitor initiation. PD-L1 level was measured via FoundationOne immunohistochemistry staining and reported as combined positive score (CPS). Additionally, next generation sequencing was performed on tumor (30/36 patients) and blood (33/36 patients) specimens via FoundationOne and Guardant360 testing platforms. Results: Out of 155 HNSCC patients treated with a PD-1 inhibitor, 36 patients demonstrated an exceptional response as defined above. 20 with CR, 9 with PR and 7 with SD. With an average follow up of 32 mo (95% CI, 26 mo-ongoing), the average OS was 33 mo (95% CI, 28 mo–ongoing) and the average PFS was 25 mo (95% CI, 20 mo-ongoing). These patients underwent an average of 27 treatments (range, 10-64 treatments to date). PD-L1 average score at 36 (95% CI, 22-49) and average TMB at 19 mut/mb (range, 0-90 mut/mb). Of 290 detected gene mutations, the most frequently mutated genes were TP53 (75%), PIK3CA (42%), CDKN2A (36%), EGFR (33%), TERT (25%), BRCA2 (22%), ERBB2 (22%), HNF1A (22%), MLL2 (22%), NOTCH1 (22%), and RAD21 (22%). Conclusions: There is limited data reporting the genomic profile of exceptional responders to PD-1 inhibitors in refractory/metastatic HNSCC. Higher TMB and single gene mutations such as TP53, PIK3CA, CDKN2A, EGFR, and TERT are frequently detected in exceptional responders and may provide future direction into the investigation of predictors of response to ICIs.
An open-label, single-center phase II trial of cadonilimab (an anti-PD-1/CTLA-4 bispecific antibody) in combination with platinum-based dual-drug neoadjuvant chemotherapy for locally advanced, resectable head and neck squamous cell carcinoma.
Authors: Fei Cao, Di Wu, PengFei Xu, Qi Fang, Zheng Zhao, Xinrui Zhang, Honghong Yan, Ke Jiang, Jian Zhou, Yan Li, Li-Xia Lu, Chunyan Chen, Fei Han, Zhiming Li, Xuekui Liu
Journal: Journal of Clinical Oncology (2024)

6044 Background: Consensus on neoadjuvant treatment strategies for resectable head and neck squamous cell carcinoma (HNSCC) is not proposed currently. Preclinical and clinical findings suggested that PD-1/CTLA-4 bispecific antibodies may have synergistic anti-tumor activity. This study aimed to explore the safety and activity of cadonilimab in combination with platinum-based dual-drug neoadjuvant chemotherapy in locally advanced, resectable HNSCC. Methods: In this open-label phase II trial, eligible patients with untreated locally advanced, resectable HNSCC (T2N2-3M0、T3-4N0-3M0; stage III-IV, AJCC 8th Edition) were enrolled to receive cadonilimab (10 mg/kg) and platinum-based dual-drug [docetaxel (75 mg/m2) plus cisplatin (60 mg/m2)] on day 1 of each 21-day cycle for three cycles, followed by surgery and postoperative adjuvant therapy. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included pathologic complete response (pCR), safety, disease-free survival (DFS), and overall survival (OS). Results: Between July 2023 and December 2023, 24 patients were enrolled (median age, 55 years [range 34–69]; 21 men [87.5%]), tumors were located in the oral cavity (10/24, 41.7%), hypopharynx (8/24, 33.3%) and larynx (6/24, 25.0%), 20 (83.3%) patients were clinical T3/4 while 10 patients (41.7%) ≥N2 . After completion of neoadjuvant therapy, the ORR was 87.5% (21/24). Of the 24 patients, 12 (50.0%) patients reached pCR. Treatment-related adverse events (TRAEs) occurred in 14 (58.3%) patients. Grade 3-4 TRAEs were reported in 4 (16.7%) patients, including rash (12.5%), pruritus (12.5%) and Guillain-Barre syndrome (4.2%). DFS and OS data were not yet mature as of the cutoff date (January 1,2024). Conclusions: Cadonilimab plus platinum-based dual-drug neoadjuvant chemotherapy achieved favorable ORR and pCR with manageable toxicities in patients with HNSCC. Follow-up is still underway to obtain long-term survival data. Clinical trial information: NCT06023875 .
Neoadjuvant immunotherapy for oropharynx cancer: Correlative studies and long-term outcomes from the CIAO trial.
Authors: Daniel McGrail, Kaiyi Li, Allison Nipper, Faye M. Johnson, Erison Santana, Diana Bell, Minjung Lee, Cara L Haymaker, Adam S. Garden, Shiaw-Yih Lin, J. Jack Lee, Maura L. Gillison, Neil D. Gross, Andrew G. Sikora, Renata Ferrarotto
Journal: Journal of Clinical Oncology (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.