bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of glutamine metabolism in CD8+PD-1+TIM-3+ T cells in ICI resistant melanoma.
Authors: Thapaliya Samjhana , Gastman Brian , Phoon Yee Peng , Li Chuan , Zhou Beiyan , Funchain Pauline , Richardson Brian , Cameron Mark , Cameron Cheryl 
Published: May 2020

e22055 Background: Immune checkpoint inhibitors (ICI) targeting checkpoints has achieved cures in half of stage IV melanoma patients yet there remains a critical need to identify why other half remain either ICI resistant or relapse. Recent studies show that multiple subpopulations of tumor-infiltrating CD8+PD-1+ T cells, previously known to be exhausted, are in fact metabolically active. We have identified a sub population of CD8+PD-1+ T cells resistant melanoma that are metabolically active, highly proliferative; and has high glutamine metabolic pathway. Rapidly proliferating cells utilize the glucose-lactic acid pathway for faster energy production and can metabolize glutamine for energy. A recent study showed that glutamine metabolism blockade improves immunotherapy response by enhancing cytotoxic T cell function. However, the role of glutamine in dysfunctional CD8+T cells has not be studied. Methods: Using patient-derived ICI resistant tumors (n = 8), tumor infiltrating lymphocytes (TILs) were isolated and sorted for total CD8+ T cells for single cell RNA sequencing, and then into CD8+PD-1+TIM-3+ T cells for bulk RNA analysis. FACS analysis was performed to assess the protein expression of SLC1A5 (a major glutamine transporter) and ki67. Seahorse Fuel Flex Test was employed to examine oxidative phosphorylation and mass spectrometry analysis was performed on sorted CD8+PD-1+TIM-3 TILs to assess the glutamine and lactic acid content. Results: A volcanic plot from bulk RNAseq data demonstrated an increase in glutamine pathway activity as well as the expression of SLC1A5 in CD8+PD-1+TIM3+ T cells compared to the peripheral CD8+ T cells. Similarly, scRNAseq analysis showed an increased expression of ki67 and SLC1A5 in MAD CD8+ T cells compared to the effector and naïve CD8+ T cells. FACS analysis of TILs gated for CD3+CD8+,showed an increased protein expression of SLC1A5 and ki67 in the PD-1+TIM-3+ population. A seahorse assay using sorted CD8+PD-1+ TIM3+ TILs from human samples confirmed an increased oxidative consumption rate (OCR) and increased dependency of glutamine metabolism in MAD CD8+ T cells compared to healthy CD8+ T cells. Importantly, mass spectrometry of CD8+PD-1+ TIM3+ T cells showed a significant increase in glutamine and lactate supporting our hypothesis that MAD CD8+ T cells have increased glutamine metabolism due to anaerobic glycolysis. Conclusions: Glutamine is a major metabolic source for rapidly proliferating CD8+PD-1+TIM-3+ dysfunctional T cells and inhibition of glutamine metabolism can be leveraged as immunotherapy in ICI resistant melanoma.
The value of lymph node ultrasound and whole body PET/CT in stage IIB/C patients prior to SLNB.
Authors: Stahlie Emma H.A. , Van Der Hiel Bernies , Bruining Annemarie , Wouters Michel W.J.M. , Schrage Yvonne , van Houdt Winan J. , Van Akkooi Alexander Christopher Jonathan 
Published: May 2020

e22079 Background: Stage IIB/IIC (pT3b-T4N0) patients are known to have high-risk primary tumors, even higher risk than some stage IIIA/B melanomas (AJCC Staging System 8th edition), however they follow the same routine to sentinel lymph node biopsy (SLNB) as more low-risk tumors. A priori the risk of finding SLNB or other metastases is much higher for these thick and/or ulcerated primary melanomas compared to the thinner ones. Guidelines are not conclusive regarding the use of preoperative imaging in these cases. Recently, a trend to more frequently use cross-sectional imaging has been noticed. However, others have previously shown that preoperative ultrasound was the most sensitive. The aim of this pilot study was to assess the value of ultrasound (US) and Positron Emission Tomography/Computerized Tomography (PET/CT) prior to SLNB for stage IIB/C (pT3b-T4N0) melanoma patients. Methods: Starting 2019-04, all patients with a pT3b melanoma or higher (8th AJCC) were included. All patients underwent US and PET/CT before their planned lymphoscintigraphy and routine SLNB. Suspected metastases were confirmed with cytologic puncture. Results: A total of 20 patients were screened. Seven patients (35%) had metastases detected by imaging: one by PET/CT, three by US and three by both imaging modalities. Three of these metastases were detected by US as well as PET/CT. All metastases were nodal. For all seven patients treatment was altered to lymph node dissection with adjuvant therapy. Of the 13 patients in whom no metastases were identified by imaging, six (46%) still had a positive sentinel node (SN). Conclusions: This study showed that this select group of patients had a high risk of metastases prior to SLNB and that all recurrences except one, were detected by ultrasound. This suggests that nodal staging with US is sufficient and can replace the need for SLNB when metastases is proven with cytology. Despite negative imaging, SLNB cannot be foregone for pT3b-pT4N0 melanoma patients, as many still have an involved SN. Cross-sectional imaging can be reserved for patients after positive cytology or SN to confirm the absence of distant visceral metastases.
Toxicities with combination BRAF and MEK inhibition in resected stage III melanoma.
Authors: Warrier Govind , Homan Morgan , Lao Christopher D. , Yentz Sarah Elizabeth , Kraft Shawna , Fecher Leslie Anne 
Published: May 2020

e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.
Predictors of extensive subclinical spread in squamous cell carcinoma.
Authors: Eversman Anna , Tracey Elizabeth , Michalik Daniel , Rodriguez Marla , Briskin Isaac , Poblete-Lopez Christine 
Published: May 2020

e22093 Background: Extensive spread of squamous cell carcinoma (SCC) is often clinically imperceptible but has a profound impact on risk of recurrence and metastasis. Accurate identification of high-risk SCC enables educated choices in treatment modality and appropriate referrals for Mohs micrographic surgery (MMS). Methods: We conducted a retrospective cohort study of 1,019 patients with SCC removal by MMS at the Cleveland Clinic. We analyzed the relationship between various patient and tumor characteristics to aggressive subclinical extension (ASE), defined as tumors requiring >3 Mohs layers to obtain clear margins. Tumor locations were grouped into zones according to the American Academy of DermatologyÕs appropriate use criteria (AUC). Results: 67 of 1,149 tumors required >3 Mohs layers for removal. Tumor grade was the only statistically significant variable, with moderately-differentiated tumors having 1.828 times the odds of ASE compared to well-differentiated tumors (95% CI = [1.026, 3.255], p = 0.041). Poorly-differentiated tumors had 4.273 times the odds of ASE compared to well-differentiated tumors (95% CI = [1.755, 10.4], p = 0.001). Conclusions: Current treatment guidelines for SCC are largely derived from data on all non-melanoma skin cancers. SCC is associated with higher metastatic potential than basal cell carcinoma (BCC), emphasizing the importance of independent analysis of SCC. The power of this study was limited by the small number of extensively spread tumors. Despite this limitation, our analysis shows poorly and moderately-differentiated tumors are correlated with a higher rate of ASE compared to well-differentiated tumors. Moderately-differentiated tumor grade is not included in the AUC, however treatment of these tumors with MMS might improve patient outcomes and minimize costs associated with recurrence. Our results show risk stratification by zone has minimal utility in identifying ASE-SCC. Improved understanding of location-based differences in tumor behavior could reveal discrepancies between SCC and BCC, enabling revised zones specific to SCC. [Table: see text]
Quantifying the additional prognostic value of sentinel lymph node status over established clinicopathologic primary tumor features for predicting survival outcomes in melanoma patients.
Authors: Lo Serigne , El Sharouni Mary-Ann , Suijkerbuijk Karijn , Ahmed Tasnia , Arjen Witkamp , Cust Anne E. , Sigurdsson Vigfús , van Diest Paul J. , Scolyer Richard A. , Van Gils Carla , Thompson John F. 
Published: May 2020

e22105 Background: Sentinel node (SN) staging not only provides important prognostic information for patients with primary cutaneous melanoma but it also assists in assessing eligibility for adjuvant systemic therapy and clinical trials. This study aimed to quantify the incremental value of SN status over established clinicopathologic prognostic factors in predicting survival outcomes. Methods: The training cohort (n = 9272) consisted of all Dutch melanoma patients who underwent SN biopsy (SNB) between 2004 and 2014. Melanoma patients having SNB during the same period were identified from the Melanoma Institute Australia (MIA) database as the validation cohort (n = 5644). Outcomes investigated included overall survival (OS), disease-free survival (DFS) and melanoma-specific survival (MSS, available for the MIA cohort only). Multivariable Cox proportional hazards analyses were performed with and without SN status and compared for each of the outcomes. The effect of adding SN status on the predictive performance of the models was quantified through discrimination index (Harrell’s C-statistic), calibration (plots) and reclassification (Net Reclassification Index (NRI)) at fixed follow-up time points. Results: In the Dutch cohort adding SN status to a model with Breslow thickness, ulceration, mitotic rate, age, gender, melanoma subtype, anatomic site and regression, improved the C-statistic from 0.72 (95% CI 0.70-0.73) to 0.76 (95% CI 0.75-0.77) for DFS and from 0.75 (95% CI 0.73-0.76) to 0.78 (95% CI 0.77-0.79) for OS. These findings were confirmed in the validation cohort, with the C-statistic increasing from 0.69 (95% CI 0.66-0.72) to 0.73 (95% CI 0.70-0.76) for DFS, 0.69 (95% CI 0.66-0.73) to 0.73 (95% CI 0.70-0.76) for OS and 0.71 (95% CI 0.69-0.73) to 0.76 (95% CI 0.74-0.78) for MSS. When setting 10% as the cut-off risk in NRI analysis, 54 Dutch and 26 MIA patients who experienced disease progression within the first 3 years after melanoma diagnosis, but were classified as low-risk patients, would have been reclassified as high-risk with addition of SN status. At the same time, 209 Dutch and 230 MIA patients who were disease-free within the first 3 years, but classified as high-risk would have been reclassified as low-risk with addition of SN status. Conclusions: Adding SN status significantly improved the predictive accuracy for OS, DFS and MSS models in melanoma patients.
Clinicopathological demographics of malignant melanoma of the vulva and vagina in Japan: Japanese Gynecologic Oncology Group (JGOG)/Japanese Skin Cancer Society (JSCS)—Intergroup Study.
Authors: Nishio Shin , Ogata Dai , Kiyohara Yoshio , Takekuma Munetaka , Mikami Mikio , Usami Tomoka , Kanao Hiroyuki , Kobayashi Eiji , Kondo Eiji , Nishino Koji , Miyamoto Yuichiro , Furusawa Akiko , Fujisawa Yasuhiro , Yamamoto Yuki , Kaji Tatsuya , Ihn Hironobu , Enomoto Takayuki 
Published: May 2020

e22106 Background: Malignant melanomas of the vulva (VuM) and vagina (VaM) represent a unique subgroup of malignant melanomas with important differences in biological properties and treatment. In Japan adequate surveys have not been performed.The objective of this study was to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. Methods: Women with invasive VuM or VaM were identified from a medical records. Data on clinician (Gynecologist or Dermatologist), age, location, node status, ulceration, mitotic count, histologic subtype, American Joint Committee on Cancer (AJCC) stage, primary surgery, and surgical margin were collected. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. Results: A total of 217 patients (pts) were identified; 109 (50.2%) had VuM and 108 (49.8%) had VaM. The median age of the subjects was 67 years (range [R], 29-96 years). Surgery was performed in 84.3% of the women with VuM and 83.3% of those with VaM. The median depth of invasion was 4.5 mm (R, 0.1-12 mm). Ulceration was documented in 47.9% (104/217) of the lesions. Nodal status was positive in 60 pts (27.6%), negative in 149 pts (68.7%), and unknown in 8 (3.7%) pts. The AJCC stage was stage I in 37 pts (17.1%), II in 106 pts (48.8%), III in 46 pts (21.2%), and IV in 28 pts (12.9%). Nodular melanoma was the most common subtype (48.8%). The median PFS was 16.8 months in pts with VuM (95% confidence interval [CI] 23.1-87.7) and 15.6 months in pts with VaM (95% CI 8.4-12.6). The median OS was 43.9 months (95% CI 60-138) in pts with VuM and 31.1 months (95% CI 24.8-45.3) in pts with VaM. Univariate analysis showed that vaginal location, nodal metastases, stage, surgery, and surgical margin were associated with poorer PFS, whereas nodal status, histologic subtype, stage, surgery, and surgical margin were associated with poorer OS. Multivariate analysis showed that only disease stage (hazard ratio [HR] = 3.09; 95% CI = 1.73-5.49) was associated with poorer PFS. Surgical margin was the only independent factor influencing OS (HR = 2.39; 95% CI = 1.48-3.80). Conclusions: The overall outcomes of VuM and VaM remain poor in Japan. In particular, the outcomes of VaM are worse than those reported previously. AJCC stage and surgical margin are important predictors of survival. Regardless of disease stage, suitable surgical resection is required. Clinical trial information: UMIN000025968.
Influence of urokinase gene knockout on tissue levels of biogenic amines in mice with melanoma.
Authors: Kaplieva Irina V. , Frantsiyants Elena M. , Surikova Ekaterina I. , Neskubina Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Nemashkalova Ludmila A. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Zakharova Natalia A. , Khokhlova Olga V. , Przhedetskaya Viktoria Yu. , Kit Oleg I. 
Published: May 2020

e22109 Background: The plasminogen activation system and biogenic amines are involved in melanoma pathogenesis, but currently, the mutual influence of the components of these systems on each other is unknown. The purpose of the study was to reveal the dynamics of biogenic amines in the brain and intact and tumorous skin (B16/F10 melanoma) in C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice with uPA gene knockout. Methods: The study included male and female C57BL/6-PlautmI.IBug-This Plau6FDhu/GFDhu mice, n = 38; the comparison group included C57BL/6 mice without uPA gene knockout, n = 61. Melanoma was transplanted under the skin of the back. Levels of biogenic amines were measured in tissues taken in week 3 of carcinogenesis by ELISA using standard test systems (Cusabio, China). Results: The total content of biogenic amines was elevated in tissues of intact C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice: in the skin – due to the noradrenaline (NA) rise by 4.8 times in males and by 4.9 times in females, histamine (H) – by 3.6 times in males and 1.6 times (p < 0.05) in females, serotonin (5HT) by 3.4 times in males and 8.3 times in females; in the brain – due to the NA rise by 3.5 times in males and 3.2 times in females, dophamine by 2.1 times in males and 2.9 times in females, while H levels declined. Distinctive features of the melanoma development in C57BL/6-PlautmI.IBug-ThisPlau6FDhu/GFDhu mice included: lower levels of adrenaline with high NA concentrations and an enhanced synthesis and inactivation of 5HTin the brain. The content of catecholamines in the tumor nodes was the same as in C57BL/6 mice, with a high concentration of H recorded in the tumor and skin, together with a high 5HT level in the skin. Conclusions: The uPA gene knockout limits the development of stress at the central regulatory and peripheral effector levels, and modulates the immune antitumor response by increasing serotonergic mediation in the brain and increasing serotonin and histamine levels in the skin of mice with B16/F10 melanoma.
A single-center, open-label clinical study to evaluate pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte stimulating factor in pediatric patients with acute lymphoblastic leukemia.
Authors: Yang Wenyu , Liu Tianfeng , Chen Xiaojuan , Guo Ye , Li Ting , Qi Benquan , Liu Fang , Chang Lixian , Ruan Min , Liu Xiaoming , Zhang Li , Zou Yao , Chen Yumei , Zhu Xiaofan 
Published: May 2020

e22501 Background: The aims of the study were to investigate the pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte colony stimulating factor(PEG-rhG-CSF) in pediatric patients with acute lymphoblastic leukemia(ALL), and compare the efficacy and safety of PEG-rhG-CSF (brand name:jinyouli) and rhG-CSF. Methods: Pediatric patients with newly diagnosed ALL who planned to use CAM (cyclophosphamide, cytarabine, 6-mercaptopurine) for chemotherapy were assigned to PEG-rhG-CSF group or rhG-CSF group. In the PEG-rhG-CSF group, PEG-rhG-CSF (100ug/kg) was injected subcutaneously once 48 hours after chemotherapy. In the rhG-CSF group, rhG-CSF (150ug/d) was injected subcutaneously daily from 48 hours after chemotherapy until the absolute neutrophil count (ANC) was≥1.0×109/L. The serum concentration of PEG-rhG-CSF was detected by enzyme-linked immunosorbent assay (ELISA). Safety and efficacy of the two groups were evaluated. Results: Between November 2015 to April 2016, 17 pediatric patients were assigned to PEG-rhG-CSF(n = 9) or rhG-CSF(n = 8) groups. The main pharmacokinetic parameters (mean±SD) of PEG-rhG-CSF group were as follows: Cmax was 353.50±136.3 ng/ml, Tmax was 44.00±20.8 h, t1/2 was 14.58± 2.2h. The PEG-rhG-CSF serum concentration and ANC curve were consistent with the mechanism of neutrophil mediated clearance. The average value of ANC nadir in PEG-rhG-CSF group was 0.18 (±0.32)×109/L, and the rhG-CSF group was 0.08 (±0.09)×109/L, there was no significant difference between the two groups ( P = 0.469). Compared with rhG-CSF, the average time of ANC recovery in PEG-rhG-CSF group was earlier (18.33±2.18 vs. 21.50±2.33, P = 0.021). There were no significant differences in the incidence of FN and infection, the duration of grade Ⅳ neutropenia and hospitalization, and the safety of the two groups. Conclusions: PEG-rhG-CSF had favorable efficacy in pediatric patients with ALL receiving chemotherapy, and there was no serious adverse event. Compared with rhG-CSF, PEG-rhG-CSF needed only once in each chemotherapy cycle, which is more suitable for pediatric patients. Clinical trial information: NCT02953730.
Body composition and treatment-related toxicity in pediatric lymphoma.
Authors: Wadhwa Aman , Barnett Kandice , Dai Chen , Richman Joshua , McDonald Andrew Michael , Williams Grant R. , Bhatia Smita 
Published: May 2020

e22503 Background: Body composition is an emerging predictor of toxicity and survival in older adults with cancer ( Shachar, Eur J Can, 2016); however, its role in pediatric cancer is not known. We examined body composition (using computed-tomography [CT] scans at the 3rd lumbar level) in children with lymphoma (Hodgkin [HL] and non-Hodgkin [NHL]) at cancer diagnosis and examined its association with treatment-related toxicities. Methods: We constructed a retrospective cohort of 87 consecutive children (HL: n = 45; NHL: n = 42) diagnosed between 2000 and 2015 (2-21y at diagnosis) with pretreatment abdominal CT scans. Body composition was assessed using sliceOmatic (TomoVision) and included skeletal muscle index (SMI, cm2/m2), skeletal muscle density (SMD: Hounsfield units [HU]), and height-adjusted total adipose tissue (hTAT: sum of visceral, intramuscular and subcutaneous adipose tissue, cm2/m2). For the analysis, we used skeletal muscle gauge (SMG = SMI x SMD, expressed per 1000 in arbitrary units [AU]) and hTAT. Sociodemographics, disease and treatment details, as well as toxicities (CTCAE v5) were abstracted from medical records. Proportion of chemotherapy cycles with grade 4 hematologic or grade 3-4 non-hematologic toxicities were calculated (percent toxicity). Generalized linear regression models were constructed to examine associations between body composition metrics and toxicities, adjusting for age at diagnosis, gender, race/ethnicity and lymphoma subtype. Results: Median age at diagnosis was 12.9y (range, 2-18.5y); 60.9% males; 60.4% non-Hispanic white. Median BMI%ile was 62 (0-99), median SMG was 2.2AU (0.9-3.7) and median hTAT was 20.1 cm2/m2 (0.04-226.7). Overall, the mean percent toxicity for grade 4 hematologic and grade 3-4 non-hematologic toxicity was 38.9% (±32.6) and 31.4% (±32.6) respectively. Correlation was poor between SMG and BMI%ile ( R2= 0.04), SMG and hTAT ( R2= -0.01) and moderate between hTAT and BMI%ile ( R2= 0.4). SMG was significantly associated with grade 4 hematologic percent toxicity ( β= -18, P= 0.007) after adjusting for hTAT and cancer type. BMI%ile was not associated with grade 4 hematologic percent toxicity ( β= -0.09, P= 0.5). Non-hematologic percent toxicity was not associated with BMI%ile, hTAT or SMG. Conclusions: In this first study of its kind, we find that children with poorer muscle quality are more likely to experience grade 4 hematologic toxicities. These findings form the basis for larger studies to incorporate body composition when developing prediction models for chemotherapy-related toxicity and disease outcomes.