bluuebunny/crossref_metadata_2025_split huggingface dataset:
A random forest model to predict the efficacy of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma based on the data from the KL167-II-05-CTP study.
Authors: Fan Guangyu , Xie Tongji , Tang Le , Gui Lin , Shi Yuankai 
Published: June 2024

e18012 Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. KL167-Ⅱ-05-CTP study had evaluated the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The results of KL167-Ⅱ-05-CTP study showed that not all patients with R/M NPC could benefit from KL-A167 therapy, and an effective model to predict the efficacy of KL-A167 is necessary. Methods: The baseline data of clinical characteristics, laboratory examination and imaging of patients with R/M NPC in KL167-Ⅱ-05-CTP study were collected, who received KL-A167 therapy. The progression-free survival (PFS) was selected as the predicted variable. Patients were randomly divided into training cohort (70%) and test cohort (30%). In the training cohort, uni-Cox regression was used to estimate the value in predicting PFS, and least absolute shrinkage and selection operator (LASSO)-Cox regression was performed to screen clinical, laboratory and imaging indexes to build random forest model. The accuracy of this random forest model was validated in the test cohort. Results: In this study, 137 patients with R/M NPC were enrolled, and the median PFS of them was 2.689 (95% confidence interval [ CI]: 1.475-4.098) months. A total of 14 indexes with P < 0.05 were selected to perform LASSO-Cox regression, and 10 indexes (blood lactate dehydrogenase, blood creatinine, left ventricular ejection fraction, body temperature, weight, blood lymphocyte count, blood chloride ion concentration, Eastern Cooperative Oncology Group performance status, blood triglyceride and blood alanine aminotransferase) were used to build prediction model. The C-index of risk score from this model was 0.820 and 0.790 in the training and test cohort, respectively. Patients were divided into the high and low risk groups according to the median risk score, and the median PFS of the high risk group was shorter than that of the low risk group (training cohort: 1.377 vs. 4.197 months, P < 0.001, hazard ratio [ HR] = 1.142, 95% CI: 1.111-1.175; test cohort: 3.475 vs. 10.984 months, P < 0.001, HR = 1.100, 95% CI: 1.060-1.142). Conclusions: In this study, a random forest model based on 10 clinical, laboratory and imaging indexes was constructed and showed a potential value in predicting the PFS of KL-A167 therapy in Chinese patients with previously treated R/M NPC, which could help to guide clinical trials and practices.
Time restricted eating (TRE) and immunotherapy outcomes in head and neck squamous cell carcinoma (HNSCC) via modulation of microbial butyrate and tryptophan metabolic pathways.
Authors: Bari Shahla , Eysha Mostafa , Alhomsi Muhammad , Hathout Mahmoud , Patel Krupal , Li Lucas , Sarfraz Humaira , Conejo-Garcia Jose , Muzaffar Jameel 
Published: June 2024

e18028 Background: Metastatic HNSCC continues to have very poor prognosis. Only a fraction of patients respond to immune checkpoint blocker therapy (ICB), with no effective treatment options for non-responders. Gut microbial composition and diversity have been associated with response to ICB in many cancers including HNSCC. We have previously demonstrated that TRE significantly improved progression free survival via modulation of gut microbiota. We herein report our mechanistic data demonstrating critical role of microbially mediated butyric and tryptophan metabolic pathways in augmenting antitumor immune response to ICB. Methods: Paired blood and stool samples, at baseline and at first response assessment, from 43 HNSCC patients enrolled in the TRE study (NCT05083416) was collected and analyzed using untargeted and targeted metabolomics, focusing on tryptophan and short chain fatty acid pathway. Further shot gun metagenomic sequencing was conducted on stool samples. Finally, we performed an in vitro luciferase cytotoxicity assay using SCC-4 human cancer cells to demonstrate TRE mediated antitumor immune response. We co-cultured MHC-I and NY-ESO-1, and NY-ESO-1-specific TCR-transduced T cells. tumor cells and the T cells under different conditions of butyrate concentration and T cell-to-tumor cell ratio (1:5, 1:10) and evaluated T cell mediated tumors killing. Results: We noted significantly higher abundance of clostridium butyricum (OR-1004, p-0.0002) with corresponding higher expression of butyrate kinase enzyme in stool of patients who observed TRE (OR-1.9, p-0.0003) vs those who did not, leading to higher concentration of fecal butyric acid and hydroxy indole acetic acid (HIAA) (OR-4.2, p-0.003), both of which were independently associated with longer progression free survival (HR-0.9, p<0.01). Higher abundance of butyric acid in gut is known to enhance the gut barrier function with consequent decrease in plasma butyrate and HIAA, lower systemic levels of which, was found to be associated with longer progression free survival in our cohort (OR-0.9, p-0.05). Both butyrate and 5HIAA are known activators of immunosuppressive aryl hydrocarbon receptor (AhR) expressed on cytotoxic CD8T cells, inhibiting CD8 mediated antitumor response. In line with our hypothesis, we observed that butyrate and 5HIAA impaired CD8 T mediated T cell killing of tumor cells in a dose-dependent manner. Conclusions: These results suggest that TRE favorably modulates ICB response via enrichment of gut microbiota with butyrate producing microbial organism, leading to increased abundance of gut butyrate and microbial tryptophan metabolites and their consequent reduction in systemic circulation, ultimately enhancing antitumor immune response.
Immune system evaluation in a cohort of Brazilian patients with head and neck squamous cell carcinoma who are non-smokers and alcoholic beverages abstainers.
Authors: Castro Gilberto , Lepique Ana Paula , Cruz Lorraynne Letycia Prado , Pasini Fatima Solange , Maistro Simone , Roela Rosimeire Aparecida , Katayama Maria Lucia Hirata , Ribeiro Ana Carolina Prado , dos Santos Alexandre Bezerra , Koike Folgueira Maria A. A. , Kowalski Luiz Paulo 
Published: June 2024

e18030 Background: Smoking and alcohol abuse are the main risk factors for head and neck squamous cell carcinoma. However, some patients do not present clear risk factors. We are studying a cohort of Brazilian patients that are non-smokers and alcoholic beverage abstainers. Brazilian people have peculiar ethnic characteristics, reflecting a miscegenation of Europeans, Africans and Amerindians. There is evidence that ethnic background may influence germline and somatic mutations, as well as tumor behavior. One of the aims is to evaluate the immune system of this cohort of miscegenated head and neck squamous cell carcinoma patients who are non-smokers and alcoholic beverages abstainers. Methods: In this prospective study, until now we have included 16 patients: 10 women and 6 men, who were non-smokers and alcoholic abstainers. All patients answered a questionnaire and collected blood, saliva and tumor samples before treatment for analysis. Self-declared skin color was mainly brown (n=8,) followed by white (n=6), black (n=1) and yellow (n=1). The median age was 56.5 years. Patients were diagnosed with oral (n=10), glotic (n=1), oropharyngeal (N=1,) lip and gingiva (n=4) carcinoma; clinical stages I (n=3), II (n=6); III (n=1) and IVA (n=5). Fourteen patients were already operated on. Results: Peripheral blood analysis revealed that within the mononuclear cell population CD16+CD66b-HLA-DR- cells, possibly NK, were significantly more frequent in patients with cancer stage III and IVA, than in patients with cancer stages I and II. There was also a significant negative correlation between the frequency of CD16+ cells in the mononuclear population and age of the patients. Finally, we observed that in the granulocyte population, patients with lesion grade I and II have 20-fold more CD16+CD66b+PD-L1+ cells than patients with lesions grade III and IV. It is possible that an IFN gamma driven response may be, in part, responsible for the induction of PD-L1 expression in granulocytes. This hypothesis is corroborated by the positive correlation between PD-L1 expression level in the granulocyte population and the frequency of CD16+CD66b- population (p=0.01, Pearson correlation 0.62). No other parameter, which included lymphocytes T and B, and monocytes, displayed correlation with clinical data. Conclusions: Our results suggest NK and myeloid cell frequency may vary in our cohort according to lesion grade as a consequence of immune responses. However, these are preliminary results, and other parameters acquisition, as well as a larger sample, will be needed for definitive conclusions.
Treatment of iodine refractory well differentiated thyroid carcinoma: Real world data from a tertiary center in Mexico.
Authors: Cervin Cristhel , Sánchez Valencia Patricia Elvira , Del Valle Delgado Karina , Cardenas Eduardo , Cervantes Guadalupe 
Published: June 2024

e18064 Background: Sorafenib and lenvatinib are the only drugs approved based on phase III clinical trials as first-line treatment in radiation-refractory, progressive, differentiated thyroid carcinoma, with limited data available for a direct comparison of these tyrosine kinase inhibitors. We aimed to evaluate the progression-free survival between the two groups treated with both medications in a Mexican tertiary center. Methods: In this retrospective study conducted from December 2015 to June 2024, we evaluated the outcomes of 38 patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, treated with sorafenib or lenvatinib. The primary outcome was the probability of progression-free survival (PFS) between both groups. Results: Eighteen patients treated with sorafenib and twenty patients with lenvatinib were included. The median age was 64.5 years, and 76% were women. Papillary histology was the most frequent (81%), and they were diagnosed at stage IV in the majority of cases (82%). More than half of the patients had previously undergone surgery, radiotherapy, and/or radioactive iodine treatment. After a median follow-up of 13.2 months, no difference in PFS was observed between the sorafenib and lenvatinib arms (HR 1.53, 95% CI 0.38-6.05, p=0.54). Conclusions: Sorafenib and lenvatinib have shown comparable efficacy in prolonging progression-free survival in Mexican patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, leading to markedly superior outcomes compared to pivotal studies.
Efficacy and safety of selpercatinib in advanced RET-altered thyroid cancers: A meta-analysis and systematic review.
Authors: Muhibullah - , Shafique Nouman , Kaur Navneet , Ahmed Jawad , Zain Sarmad , Naqvi Syed Mujtaba Ali , Bajwa Shammas , Nawaz Hassan , Ur Rehman Atta , Haider Ali , Ghaffar Ali , Javeed Zainab , Iqbal Abdul Ghani , Ehsan Amna , Khanal Prajjwal , Shafique Adeena , Shafiq Iqra , Kumar Besham , Hussain Rida , Rizwan Umer 
Published: June 2024

e18073 Background: Selpercatinib is a highly selective RET inhibitor that is used for the treatment of RET-mutant medullary thyroid cancers, but its efficacy and safety is not fully understood. Our objective is to summarize available literature on the safety and efficacy profile of Selpercatinib. Methods: A search was conducted on PubMed, Embase and Cochrane from foundation to 31st January 2024. Patients aged above 18 with Advanced RET-Altered Medullary Thyroid Cancers who received Selpercatinib were identified. Data abstraction was done based on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Analysis was done using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Four studies were identified that reported the use of Selpercatinib in Advanced RET-Altered Medullary Thyroid Cancers. Our analysis showed that the pooled proportion of objective response rate and complete response rate was 74.8% (95% CI: 70.1% – 79%) and 4.9% (95% CI: 3.1% – 7.7%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 93.4% (95% CI: 90.4% – 95.6%) and 46.2% (95% CI: 41.1% – 51.3%) respectively. Conclusions: Selpercatinib is a novel RET inhibitor which has potential use against RET-Altered Thyroid Cancers. It has an overall acceptable safety and efficacy profile. However it requires further studies to establish its adverse effects and clinical application. [Table: see text]
Timing of allogeneic hematopoietic cell transplantation for myelofibrosis and other myeloproliferative neoplasms.
Authors: Mercer Joshua S. , Bradbury Claire I. , Thomas Samantha M. , Ramalingam Sendhilnathan , Gasparetto Cristina , Choi Taewoong , Sung Anthony D. , Sarantopoulos Stefanie , Long Gwynn Douglas , Alyea Edwin , Horwitz Mitchell E. , Chao Nelson Jen An , Hong Sanghee 
Published: June 2024

e18517 Background: Myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS)/MPN overlap syndromes are rare hematopoietic malignancies in which allogeneic hematopoietic cell transplantation (HCT) is the only treatment with curative potential. Even for higher risk patients, the optimal timing for HCT is largely unknown. We interrogated HCT outcomes of myelofibrosis (MF) and the rest of MPN, MDS/MPN overlap based on the timing of HCT from diagnosis (Dx) to help oncologists determine the optimal timing to refer patients for HCT. Methods: This retrospective, single-center study obtained data from our HCT database. We included adult (>18 years; y) patients who received their first allogeneic HCT between 2015 and 2022 for initial Dx of MPN or MDS/MPN overlap. We included all donor types and graft sources. Analysis was separated by MF vs. others (other MPN and MDS/MPN) to account for fibrotic vs proliferative nature of disease progression and sample size. The primary variable was the time from Dx to HCT. The primary endpoint was overall survival (OS) from HCT. Secondary endpoints were progression free survival (PFS) and non-relapse mortality (NRM) from HCT. Results: 46 patients (n=27 for MF, n=19 for others) were included. 59% were male (56% for MF, 63% for others). The median age at HCT for MF was 57y (range 45-72) and for others was 63y (32-75). For patients with MF and others, 85% and 84% received myeloablative conditioning, respectively. In the MF group, all patients had PBSC grafts and 37% of grafts were from match-related donors; in the others group, 89% had PBSC grafts (11% had BM grafts) and 53% of grafts were from match-related donors. The median time from Dx to HCT for patients with MF was 28 months (m; range 4-166) and for others was 11m (2-423). In the MF group, those whose HCT <1y from Dx had improved OS (Table) and PFS (1y, 83.3% vs. 53.3%, p=0.031) compared to HCT ≥1y after Dx. However, no differences were found in OS or PFS for <6m vs. >6m from Dx to HCT. No differences in OS/PFS were seen based on the timing of HCT in the others group. Conclusions: Patients with MF, but not with other MPN or MDS/MPN, who received allogenic HCT <1y from Dx had significantly improved OS and PFS. Our results suggest that early referral to HCT after confirmation of marrow fibrosis for higher risk MF may influence HCT outcomes positively. However, lack of improvement in OS/PFS at 6m suggests that addressing individual risks and initiating appropriate therapies for MF first may more effectively balance risks of post-HCT complication with disease progression. Additional studies investigating timing of HCT will help oncologists to direct management of MPN and MDS/MPN overlap. [Table: see text]
Relationship of body mass index and plasma imatinib levels in CML patients and mitigation of clinical impact using PK-guided dosing strategy.
Authors: Maroselli Paul , Fanciullino Raphaelle , Colle Julien , Farnault Laure , Rocher Pauline , Venton Geoffroy , Costello Régis , Ciccolini Joseph 
Published: June 2024

e18522 Background: Imatinib is a mainstay of treatment for patients with chronic myeloid lymphoma (CML). Exposure-response relationships have been demonstrated and trough levels between 800 and 1000 ng/ml are usually associated with Major Molecular Response (MMR), prolonged survival and acceptable safety. The extent to which body mass index (BMI) might influence drug pharmacokinetics (PK) and clinical outcome remains to be investigated. Methods: Therapeutic drug monitoring was performed in 60 adult patients (56 years, M33/27F) starting imatinib (400 mg QD) for CML, and baseline deviation from target Cmin was used to subsequently adjust dosing using Monolix software. Baseline BMI was calculated and collected along with other patient characteristics and comedications likely to alter imatinib PK. Response (MMR at 3 months) and drug-related toxicity (CTCAE grading) were recorded. Patients were divided into three subgroups: BMI<18.5; 18.5<BMI<24.5, and BMI>24.5. The association between BMI and trough imatinib levels at baseline, further differences in toxic events and response rate between cohorts, as well as differences in dosing after PK-guided dose adjustment, were all tested using appropriate statistical analysis. Results: Mean imatinib trough levels at baseline were 1172 (754-4737), 870 (276-1767) and 820 (334-2217) ng/ml for patients with BMI<18.5, 18.5<BMI<24.5 and BMI>24.5, respectively. Patients with BMI<18.5 were statistically overexposed (p<0.01, ANOVA). Conversely, there was a trend towards lower exposure in patients with BMI>24.5, but this was not statistically significant. Multivariate analysis confirmed that low BMI was an independent factor for overexposure with imatinib. After PK-guided dosing, a statistically significant difference in dosing after correction was observed, as overexposed patients had their dose reduced to an average of 330 mg QD, whereas underexposed patients had their dose increased to an average of 500 mg QD (p<0.01, paired t-test). Consequently, when comparing in the three different cohorts the incidence of both response and toxic events, no difference was observed among patients (p=0.33 and p=0.911 for efficacy and toxicity respectively, Chi-2 test). Conclusions: Low BMI (<18.5) puts patients at risk of significant overexposure to imatinib, whereas there is a trend towards lower exposure in patients with high BMI (>24.5). This could potentially lead to either increased toxicity or lack of efficacy is no adjustment in dosing is performed. Here, TDM with subsequent adaptive dosing helps to correct the dose according to the initial deviation from target, thus smoothing the clinical impact of the differences in exposure observed at the start of treatment.
Dasatinib versus high-dose imatinib for chronic-phase chronic myeloid leukemia: A meta-analysis of randomized control trials.
Authors: Zafar Fabeha , Shivakumar Divya , Wankhade Diptish , Poombal Dr. , Winayak Rahul , Malik Ghulam Mustafa Ali , Mahapatra Shruti Sagar , G.C. Shasan , Ashraf Laraib , Huynh Truc , Mylavarapu Maneeth , Haider Ali 
Published: June 2024

e18523 Background: Chronic Myeloid Leukemia (CML) is one of the few cancers with a unique and identifiable genetic mutation. The issue of imatinib resistance is becoming increasingly significant in patients with chronic phase chronic myeloid leukemia (CP-CML). Methods: We systematically searched Pubmed/MEDLINE, EMBASE, and Cochrane Library from inception through March 2023 to analyze the published literature of randomized control trials (RCT) regarding patients with CP-CML resistant to imatinib. The review was carried out according to the PRISMA guidelines, and the review protocol was registered at PROSPERO (CRD42023422749). The screening was done to include studies with the following criteria: 1) Randomized control trials; (2) comparisons between high-dose imatinib and dasatinib; (3) patients with imatinib-resistant CP-CML; and (4) measurements of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR). The quality assessment of the included studies was carried out using JBI's (Joanna Briggs Institute's) RCT checklist. Risk ratios were used to compare the effects of dasatinib vs high dose imatinib with respect to outcomes on MMR and CCyR. Data was analyzed using R version 6.2.1. A p-value of <0.05 was considered statistically significant. Results: We included three studies totaling 929 patients. 585 (62.9%) patients were males. There is a statistically significant improvement in MMR (RR 1.71, 95% CI 1.09 to 2.69, p=0.021, I. = 52%) and an increase in the likelihood of achieving a CCyR (RR 1.24, 95% CI 0.90 to 1.71, p=0.197, I. =74%). Conclusions: Dasatinib shows potential as a management in CP-CML patients with imatinib resistance. However, these results should be interpreted cautiously, and further validation needs to be done with high-quality, large-scale cohort studies or clinical trials to address the safety of dasatinib.
Myelofibrosis prognostic models validated in an underserved minority population: A retrospective analysis.
Authors: Kamel Josette Mary , Yan John , Goldfinger Mendel , Feldman Eric J. , Konopleva Marina , Mantzaris Ioannis , Shastri Aditi , Kornblum Noah , Gritsman Kira , Sica Alejandro R. , Shah Nishi , Cooper Dennis , Verma Amit , Goel Swati 
Published: June 2024

e18529 Background: Contemporary prognostic models for myelofibrosis (MF) risk stratify patients using a heterogeneous composition of clinical and genetic factors. Little is known regarding how these scores perform in underserved populations. Our study assesses how well current models stratify risk at an inner-city tertiary care center which carries unique challenges including increased diversity, later disease presentation, and less access to healthcare resources. Methods: We retrospectively reviewed 88 MF patients referred to our center in the Bronx, NY between 2000 and 2023. Clinical and genetic data were used to calculate prognostic scoring for DIPSS, DIPSS plus, MIPSS70, MIPSSV2, and GIPSS. Overall survival (OS) was calculated from the time of diagnosis and non-deceased patients were censored at last follow-up. Patients with missing clinical or genetic data were excluded from individual analysis. Models were assessed via univariate and multivariate cox proportional hazards analysis followed by concordance analysis. Results: Mean age of the cohort was 66 years (range 29-88) with median survival of 7.7 years. Ethnicities included non-hispanic white (NHW) [30 (34.1%)], NH black [23 (26.1%)], NH asian [6 (6.8%)], and hispanics of all races [22 (25%)] (unknown n=7). DIPSS (n= 88, HR 1.77, CI 1.22 - 2.41, p-value = 0.0001), DIPSS plus (n=83, HR 1.54, 1.15-2.07, p = 0.0033), MIPSS70V2 (n=68, HR 2.06, CI 1.23 - 3.61, p = 0.0088), and GIPSS (n=69, HR 2.73, CI 1.24 - 3.78, p = 0.0063) were significantly associated with OS based on univariate analyses. Both DIPSS and GIPSS were significant even upon adjustment for each other (p=.009 and p=.043 respectively). MIPSS70 (n=73, HR 1.87, CI .93 - 3.88, p = 0.0842) did not meet significance. In terms of predictive accuracy based on C-index scores, DIPSS and GIPSS combined analysis scored highest (0.773), followed by GIPSS (.7226), DIPSS (0.719), MIPSSV2 (0.717), DIPSS Plus (0.6495), then MIPSS70 (0.6414). Conclusions: Our study shows that GIPSS, DIPSS, DIPSS plus, MIPSSV2 all function as valid prognostic models in the inner-city setting and that integrating both clinical and genetic models may have higher predictive value than either individual model alone. Additionally, GIPSS predicted superior survival outcomes to what was observed in our cohort for higher risk categories, prompting the need for further investigation. [Table: see text]