bluuebunny/crossref_metadata_2025_split huggingface dataset:
A clinical study of inferior alveolar nerve damage caused by Carnoy’s solution used as a complementary therapeutic agent in a cystic lesion
Authors: Jo Hyun-Jun , Kim Hee-Youl , Kang Dong-Cheol , Leem Dae-Ho , Baek Jin-A , Ko Seung-O 
Published: May 2020

Abstract
Background
Cyst enucleation, which extracts only the tumor with the application of Carnoy’s solution (CS), has been suggested as a conservative treatment with a low recurrence rate and morbidity. However, there has been a concern that CS’s contact with inferior alveolar nerve (IAN) can cause neurons to degenerate and cause sensory dysfunction. The purpose of this retrospective cohort study aimed to investigate the neurosensory function after surgical treatment with or without the application of CS.

Methods
While controlling the effects of sex, age, follow-up period, and invasion size of the tumor, we performed the binary logistic regression analysis to examine whether or not the sensory function of the patients who were treated with CS (n = 19) for the cyst enucleation procedure was significantly different from those who were not treated with CS (n = 58) at the end of the follow-up period.

Results
The logistic regression result showed that the use of CS was not significantly related to the normalness of sensory function at the end of the follow-up period. Rather, the invasion size of the cyst was significantly associated with sensory dysfunction.

Conclusions
CS may be used for patients who are diagnosed with OKC and UAM without much fear of its impact on sensory dysfunction. However, a small number of patients who were treated with CS experienced severe sensory damage and did not recover at the end of the follow-up period, suggesting the need for further analysis of these patients.
Learning principles of accounting in ICT-supported learning environments of Malaysian secondary schools: future-oriented approach
Authors: Tan Boon See , Wong Su Luan 
Published: May 2020

AbstractThis research was undertaken to identify the learning approaches used by Malaysian secondary school students of Principles of Accounting in the context of ICT-supported learning environments. The revised Two-Factor version of the Learning Process Questionnaire (R-LPQ-2F) was adapted to appraise the learning approaches used, while the Technology-Rich Outcomes-Focused Learning Environment Inventory (TROFLEI) was adapted to obtain the perceptions of students in ICT-supported learning environments which practising the ICT-pedagogy. The sample for the study comprised 371 Form Four Malaysian students. There were indications from this study that students employed the deep approach to learning Principles of Accounting; whereas the surface approach was not discernible. Only two scales measured the sub constructs of surface motive and surface strategy, namely aim for qualification and minimising scope of study merged and evolved into what is referred to as the future-oriented approach in this study. Aiming for qualification as a motive is complemented by a non-surface learning strategy of non-minimisation of scope of study, i.e. learning beyond the minimum scope. The future-oriented approach was influenced by socio-cultural and educational contextual factors in Malaysia. The findings also reflected the influence of ICT-supported learning environment perceptions on learning approaches.
Does a 6-point scale approach to post-treatment 18F-FDG PET-CT allow to improve response assessment in head and neck squamous cell carcinoma? A multicenter study
Authors: Bonomo P. , Merlotti A. , Morbelli S. , Berti V. , Saieva C. , Bergesio F. , Bacigalupo A. , Belgioia L. , Franzese C. , Lopci E. , Casolo A. , D’Angelo E. , Alterio D. , Travaini L. , Berretta L. , Pirro V. , Ursino S. , Volterrani D. , Roncali M. , Vigo F. , Cicchetti S. , Scalone F. , Belli G. , Cauda S. , Desideri I. , Russi E. , Livi L. , Bianchi A. 
Published: May 2020

Abstract
Purpose
Response assessment to definitive non-surgical treatment for head and neck squamous cell carcinoma (HNSCC) is centered on the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET-CT) 12 weeks after treatment. The 5-point Hopkins score is the only qualitative system available for standardized reporting, albeit limited by suboptimal positive predictive value (PPV). The aim of our study was to explore the feasibility and assess the diagnostic accuracy of an experimental 6-point scale (“Cuneo score”).

Methods
We performed a retrospective, multicenter study on HNSCC patients who received a curatively-intended, radiation-based treatment. A centralized, independent qualitative evaluation of post-treatment FDG-PET/CT scans was undertaken by 3 experienced nuclear medicine physicians who were blinded to patients’ information, clinical data, and all other imaging examinations. Response to treatment was evaluated according to Hopkins, Cuneo, and Deauville criteria. The primary endpoint of the study was to evaluate the PPV of Cuneo score in assessing locoregional control (LRC). We also correlated semi-quantitative metabolic factors as included in PERCIST and EORTC criteria with disease outcome.

Results
Out of a total sample of 350 patients from 11 centers, 119 subjects (oropharynx, 57.1%; HPV negative, 73.1%) had baseline and post-treatment FDG-PET/CT scans fully compliant with EANM 1.0 guidelines and were therefore included in our analysis. At a median follow-up of 42 months (range 5-98), the median locoregional control was 35 months (95% CI, 32-43), with a 74.5% 3-year rate. Cuneo score had the highest diagnostic accuracy (76.5%), with a positive predictive value for primary tumor (Tref), nodal disease (Nref), and composite TNref of 42.9%, 100%, and 50%, respectively. A Cuneo score of 5-6 (indicative of residual disease) was associated with poor overall survival at multivariate analysis (HR 6.0; 95% CI, 1.88-19.18; p = 0.002). In addition, nodal progressive disease according to PERCIST criteria was associated with worse LRC (OR for LR failure, 5.65; 95% CI, 1.26-25.46; p = 0.024) and overall survival (OR for death, 4.81; 1.07-21.53; p = 0.04).

Conclusions
In the frame of a strictly blinded methodology for response assessment, the feasibility of Cuneo score was preliminarily validated. Prospective investigations are warranted to further evaluate its reproducibility and diagnostic accuracy.
Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.
Authors: Eggermont Alexander M. , Blank Christian U. , Mandalà Mario , Long Georgina V. , Atkinson Victoria , Dalle Stéphane , Haydon Andrew Mark , Meshcheryakov Andrey , Khattak Muhammad , Carlino Matteo S. , Sandhu Shahneen Kaur , Puig Susana , Ascierto Paolo Antonio , Van Akkooi Alexander Christopher Jonathan , Krepler Clemens , Ibrahim Nageatte , Marreaud Sandrine , Kicinski Michal , Suciu Stefan , Robert Caroline 
Published: May 2020

10000 Background: We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. Based on 351 recurrence-free survival (RFS) events and at a median follow-up of 1.25 years (yrs), pembrolizumab improved RFS (hazard ratio (HR) 0.57, P<0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA. Methods: Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). A total of 1019 pts were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. The 2 co-primary endpoints were RFS in the intention-to-treat overall population and in pts with PD-L1-positive tumors. Here, we report an updated RFS analysis based on a longer follow-up. Results: Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. At 3.05-yr median follow-up, pembrolizumab (190 RFS events) compared with placebo (283 RFS events) prolonged RFS, in the overall population and in the PD-L1 positive tumor subgroup (see Table). RFS was consistently prolonged across subgroups, in particular according to AJCC-7 staging, BRAF-V600 E/K mutation status. Conclusions: Pembrolizumab, administered at 200 mg every 3 weeks for up to 1 year as adjuvant therapy, provided, at a 3-yr median follow-up, a sustained improvement in RFS, which was clinically meaningful, in resected high-risk stage III melanoma. This improvement was consistent across subgroups. In the overall population, the 3-yr cumulative incidence of distant metastasis being the first recurrence was 22.3% (pembrolizumab group) vs 37.3% (placebo group) (HR 0.55, 95% CI 0.44-0.69). Clinical trial information: NCT02362594. [Table: see text]
Using machine learning to predict immunotherapy response in advanced melanoma.
Authors: Johannet Paul , Coudray Nicolas , Donnelly Douglas M. , Jour George , Illa-Bochaca Irineu , Xia Yuhe , Johnson Douglas Buckner , Wheless Lee E , Patrinely James Randall , Pavlick Anna C. , Weber Jeffrey S. , Zhong Hua , Tsirigos Aristotelis , Osman Iman 
Published: May 2020

10010 Background: Several predictors of response to checkpoint inhibitors show potential, but use pathological assays and/or molecular characterization, which limits their clinical utility outside of the academic setting. We aimed to develop a streamlined approach by leveraging information immediately available through standard care. Here, we present a computational method that integrates deep learning on histology specimens with clinicodemographic variables to predict treatment outcomes in advanced melanoma. Methods: We used hematoxylin and eosin (H&E) sections from 72 patients ( n= 153 slides) from New York University (NYU) to build a Segmentation Classifier that distinguishes tumor, lymphocyte, and connective tissue. Using pre-treatment H&E slides from 121 NYU patients ( n =302 slides), we trained a Response Classifier to predict response by selectively analyzing tumor regions. We then developed a logistic regression classifier that combines neural network output with clinicodemographic variables. The classifiers were tested on an independent cohort of 32 patients from Vanderbilt University ( n =42 slides). Area under the curve (AUC) was calculated as a measure of prediction accuracy. Results: The Segmentation Classifier distinguished tumor, lymphocyte, and connective tissue with AUCs 0.886-0.984. For the Response Classifier, optimal learning conditions were identified through training on NYU patients and testing on Vanderbilt patients (AUCs 0.685 and 0.728, respectively). The fully trained Response Classifier performed with AUC 0.711 on Vanderbilt patients. The logistic regression model performed with enhanced prediction accuracy with AUC 0.803 on NYU patients and AUC 0.793 on Vanderbilt patients. Conclusions: Histology slides and patients’ clinicodemographic characteristics are readily available through routine standard of care and have the potential to predict immunotherapy response. Our approach is time-efficient, reproducible, and requires minimal resource allocation, thus overcoming multiple common barriers to generalizability for contemporary biomarkers.
Final analysis of relapse-free survival in a multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine after resection of high-risk melanoma.
Authors: Slingluff Craig L. , Blumenstein Brent A. , Lewis Karl D. , Andtbacka Robert Hans Ingemar , Hyngstrom John Robert , Milhem Mohammed M. , Markovic Svetomir , Hamid Omid , Hernandez-Aya Leonel Fernando , Bowles Tawnya Lynn , Philips Prejesh , Jang Sekwon , Lutzky Jose , Bar Anna , Beitsch Peter D. 
Published: May 2020

10017 Background: Seviprotimut-L is a vaccine prepared from antigens of 3 human melanoma cell lines, administered with alum. Prior formulations induced T cell and antibody responses and improved survival in a small phase II clinical trial. Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study, a three part, Phase III clinical program), was a multicenter, double-blind, placebo-controlled trial to assess efficacy of seviprotimut-L, with the primary endpoint of relapse-free survival (RFS). The goal of Part B1 was to guide design of the pivotal Part B2. Methods: Patients with AJCC v7 stage IIB-III cutaneous melanoma, after surgical resection, age 18-75, ECOG PS 0-1, were randomized 2:1 to seviprotimut-L 40 mcg or placebo, injected subcutaneously every 2 weeks x 5, then monthly x 4, then every 3 months x 9. Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered for assessment of RFS, with target hazard ratio (HR) of 0.625, one-sided alpha of 0.10, and power 80%. Final data are presented. Results: 347 patients were randomized. Arms were well-balanced. Treatment-related adverse events (AEs) led to discontinuation in 0.4% and 0%, respectively, for vaccine and placebo arms. There were no treatment-related SAEs. By intent-to-treat (ITT) analysis, RFS was not significantly longer for seviprotimut-L in the full study population but trended toward benefit (HR 0.88). Subgroup analysis based on planned stratification revealed the hazard ratio (HR) for the Stage IIB/IIC subset (randomization stratum, n=111) to be 0.65 (95% CI [0.37, 1.17]), favoring seviprotimut-L. Age can decrease immune competence: RFS was longer with vaccine for patients age <60 overall (N = 191, HR = 0.64 [0.38, 1.08]) and among Stage IIB/C patients (N = 52, HR = 0.32 [0.12, 0.86]). The effect modification interaction p value for age for stage IIB/IIC patients was 0.056. In a multivariable RFS model, for IIB/IIC patients <60 with ulceration (n=38), HR = 0.209 [0.07,0.61]. For overall survival, for patients < 60, HR = 0.41 [0.33,1.14] (n=191, 19 deaths) and for those ≥60, HR = 0.92 [0.39,2.12] (n = 156, 24 deaths). Conclusions: Seviprotimut-L is very well-tolerated. Subgroup efficacy analyses identified populations who may benefit from Seviprotimut-L: those with Stage IIB/IIC melanoma and those under age 60. These data support design of the definitive part B2 of the MAVIS phase III trial to test seviprotimut-L for stage IIB/C patients, with stratification by age and ulceration. Clinical trial information: NCT01546571.
The impact of BRAF mutation status on clinical outcomes with single-agent PD-1 inhibitor versus combination ipilimumab/nivolumab.
Authors: Ma Vincent The-Luc , Daignault Stephanie , Waninger Jessica , Fecher Leslie Anne , Green Michael , Alva Ajjai Shivaram , Lao Christopher D. 
Published: May 2020

10024 Background: Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for BRAF mutant metastatic melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens. Our aim was to better assess if BRAF mutation status has any impact on survival to combination ipilimumab/nivolumab (I/N) versus single-agent PD-1 inhibitor (PD-1i). Methods: We performed a single center, retrospective analysis on a cohort of patients diagnosed with metastatic or unresectable melanoma from 2012 to 2019 at the University of Michigan who were treated with standard I/N or PD-1i (nivolumab or pembrolizumab). A univariate analysis of progression free survival (PFS) and overall survival (OS) was stratified by treatment type and BRAF mutation status. A multivariate Cox regression of survival was used to compare the effects of the treatment groups adjusted by BRAF status, age, gender, pre-treatment LDH level, prior treatment status, and brain metastases status. Results: 323 patients were identified. 132 had BRAF V600 mutation and 191 had BRAF wildtype (WT) status. 138 patients received I/N and 185 patients received PD-1i. In our univariate analysis, there was no difference in PFS [HR: 0.72, 95% CI, 0.46 – 1.13] or OS [HR: 0.78, 0.44 – 1.38] with I/N versus PD-1i in the BRAF mutant cohort, but there was improved PFS [HR: 0.55, 0.35 – 0.88) and OS [HR: 0.52, 0.28 – 0.95] with I/N compared to PD-1i in the BRAF WT group. In the multivariate analysis, the BRAF WT group continued to show PFS benefit with I/N compared to PD-1i [HR: 0.57, 95% CI, 0.35 – 0.95], but the OS benefit no longer achieved statistical significance [HR: 0.54, 0.28 – 1.03]. Conclusions: Our study results were discordant with the observation in the landmark CheckMate 067 trial, which noted improved PFS and OS with I/N compared to nivolumab alone in the BRAF mutant group and no difference in the BRAF WT group. In our real-world retrospective analysis, I/N over PD-1i should be considered as initial immunotherapy for metastatic melanoma patients regardless of BRAF mutation status, but even more favorably in BRAF WT.
Initial report of treatment of uveal melanoma with hepatic metastases with yttrium90 internal radiation followed by ipilimumab and nivolumab.
Authors: Minor David R. , Sato Takami , Orloff Marlana M. , Luke Jason J. , Eschelman David J. , Gonsalves Carin F. , Adamo Robert D. , Tong Ricky T , Char Devron H. , Anne Rani , Kim Kevin B. 
Published: May 2020

10025 Background: Hepatic metastases from uveal melanoma have no established therapy, with a median survival of only 6-12 months. To date therapy with checkpoint inhibitors has yielded minimal results. To take advantage of possible synergy between radiation and immunotherapy we treated patients with yttrium90 internal radiation followed by immunotherapy. Methods: Patients received yttrium90 (Sir-Spheres) via hepatic artery infusion in two treatments, one to each lobe 3-4 weeks apart, followed in 3-6 weeks by ipilimumab and nivolumab for 4 doses, then nivolumab maintenance. Results: We are presenting interim results because of the excessive toxicity seen when these FDA-approved modalities were used in sequence with the FDA-approved dosages. Initially dosing of yttrium90 (Y90) followed the package insert “BSA method” but after 8 patients we had 5 cases of grade 3-4 hepatic toxicity; in 4 cases the toxicity was observed after just the Y90. One case of cirrhosis occurred in a patient whose liver received 40-45Gy; her cirrhosis was felt most likely due to the Y90. Y90 dosing was then reduced to limit dosage to normal liver to 35Gy, and none of the next 5 patients have had more than grade 2 hepatic toxicity. Dosage to the normal liver is approximated by the MIRD formula: Actual delivered liver dose [Gy] = 50 * Administered activity [GBq] * (1 – Lung shunt fraction) / kg of treated liver. If calculated dose was > 35GY, dosage in GBq is reduced proportionally. Toxicity in the first 5 patients to receive immunotherapy included one grade 4, two grade 3 and two grade 2 hepatic toxicities, and only 3 of the 5 patients received more than one dose of ipilimumab. We then reduced dosing of ipilimumab from 3mg/kg x 4 to 1mg/kg x 4 because of this excessive autoimmune toxicity. Of 13 patients, 10 received both Y90 and immunotherapy, and 3 had responses (1 CR, 2 PR) with 3 patients stable > 5months. Median progression-free survival for all patients is 27 weeks and median overall survival is greater than 48 weeks. Treatment with Y90 produced an over 50% fall in peripheral blood lymphocytes which was reversed in most patients by the immunotherapy. Conclusions: With dose modifications this therapy appears feasible and objective tumor responses were seen. Sequential therapy with Y90 and immunotherapy appears tolerable if radiation to normal liver is limited to 35Gy and ipilimumab dose is 1mg/kg. Clinical trial information: NCT02913417.
Association between complete response and survival in advanced melanoma treated with talimogene laherparepvec (T-VEC) plus ipilimumab (ipi).
Authors: Chesney Jason Alan , Puzanov Igor , Collichio Frances A. , Milhem Mohammed M. , Hauschild Axel , Yi Min , Bhatta Sumita , Ismail Rubina , Garbe Claus , Singh Parminder , Mehnert Janice M. 
Published: May 2020

10029 Background: This is the first randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor for advanced melanoma. At the 3-year (yr) follow-up, the combination (combo) of T-VEC and ipi demonstrated durable and statistically superior objective response rate (ORR) over ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% Cl, 1.6–6.0; P = 0.002). Complete response (CR) rate was 21.4% with the combo and 6.0% with ipi. Median overall survival (OS) was not reached in either arm. In this post hoc analysis, we utilized the 3-yr landmark data to explore the relationship between CR and OS in the combo arm. Methods: Pts with unresectable, stage IIIB-IV melanoma were randomized 1:1 to receive combo or ipi alone. T-VEC was administered intratumorally on day 1 of week (wk) 1 at 106 plaque-forming units (PFU)/mL followed by subsequent doses at 108 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were OS, progression-free survival, and safety. Results: 198 pts were randomized (98 to combo; 100 to ipi). As of February 25, 2019, the median follow-up time was 40.0 mos (range: 0.2–63.7) for the combo arm. Among 98 pts who received combo, 21 (21.4%) had a best overall response of CR including 8 who converted from an initial partial response (PR), 15 (15.3%) had PR, 19 (19.4%) had stable disease, 30 (30.6%) had progressive disease, and 13 (13.2%) were unevaluable. Of 21 pts achieving CR, 17 (81%) had ECOG status of 0, 16 (76.2%) had stage IIIB-IVM1a disease, and 16 (76.2%) had no visceral metastases. Median duration of CR was not reached (range: 5.4[+]–58.2[+] mos); 19 of 21 CRs lasted more than 6 months. The baseline tumor burden was lower in pts with CR than in those with non-CR. Median OS was not reached in pts with CR (range: 25.1[+]–63.7[+] mos) and was 47.6 mos (range: 0.2[+]– 63.7[+] mos) in pts with non-CR (Log-rank P = 0.0005). The Kaplan–Meier estimated 3-year OS rate was 100.0% for patients with CR and 52.3% for those with non-CR. Conclusions: CR rate was higher with T-VEC plus ipi than with ipi alone in pts with advanced melanoma (21.4% vs. 6.0%). In the combo arm, CR was associated with prolonged OS, and pts with CR tended to have better ECOG performance status, earlier-stage disease, and lower baseline tumor burden, as compared with those with non-CR. Clinical trial information: NCT01740297.